MXPA06000875A - Azepine derivatives as pharmaceutical agents - Google Patents

Abstract

Compounds, compositions and methods are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder related to the activity of the receptors.

Description

AZEPINE DERIVATIVES AS PHARMACEUTICAL AGENTS FIELD OF THE INVENTION Compounds, compositions and methods are provided for modulating the activity of the receptors and for the treatment, prevention, or improvement of one or more symptoms of diseases or disorders related to the activity of the receptors.

BACKGROUND OF THE INVENTION Nuclear Receptors Nuclear receptors are a superfamily of regulatory proteins that are structurally and functionally related and are receptors for, for example, steroids, retinoids, vitamin D, and thyroid hormones (see for example, Evans (1988)). Science 240: 889-895). These proteins bind to the elements that are driven in the promoters of their targeting genes and modulate the expression of the gene in response to the ligands of the receptors. Nuclear receptors can be classified based on their DNA binding properties (see, for example, Evans, supra and Glass (1994) Endocr. Rev. 15: 391-407). For example, a class of nuclear receptors includes glucocorticoids, estrogen, androgen, progestin, and mineralocorticoid receptors that are linked as Ref: 169720 homodimers to hormone response elements (HREs) organized as inverted repeats (see, for example, Glass supra). A second class of receptors that include those activated by retinoic acid, thyroid hormone, vitamin D3, peroxisome fatty acid proliferations (ie peroxisome proliferator activated receptor (PPAR)) and ecdysone, bind to HREs as a heterodimer with a standard common, retinoid X receptors (ie, RXRs, also known as 9-cis retinoic acid receptors, see for example, Levin et al. (1992) Nature 355: 359-361 and Heyman et al. (1992) Cell 68 : 397-406). RXRs are unique among nuclear receptors in that they bind to DNA as a homodimer and are required as a heterodimeric partner for a variety of additional nuclear receptors to bind DNA (see for example, Mangelsdorf et al. (1995) Cell 83: 841 -850). The last receptors, called the class II nuclear receptor subfamily, include many that are established or implied as important regulators of the expression gene. There are three RXR genes (see for example, Mangelsdorf et al. (1992) Genes Dev. 6: 329-344) that encode RXRa, -β and - ?, all capable of heterodimerizing with any of the class II receptors despite which appear to have preference for different RXR subtypes by in vivo standard receptors (see, for example, Chiba et al (1997) Mol Cell Biol. 17: 3013-3020).

In the adult liver, RXR is the most abundant of the three RXRs (see, for example, Mangelsdorf et al. (1992) Genes Dev. 6: 329-344), suggesting that it might have a prominent role in liver functions that involve regulation by nuclear class II receptors. See also, Wan et al. (2000) Mol. Cell. Biol 20: 4436-4444.

Orphan Nuclear Receptors Included in the nuclear receptor superfamily of regulatory proteins are nuclear receptors for whom the ligand is known and those lacking known ligands. Nuclear receptors that fall into the latter category are referred to as orphan nuclear receptors. The search for activators for orphan receptors has led to the discovery of previously unknown signaling pathways (see, for example, Levin et al., (1992), supra and Heyman et al., (1992), supra). For example, it has been reported that bile acids that are involved in physiological processes such as cholesterol catabolism are ligands for the X \ farnesoid receptor (infra). Since it is known that intermediary metabolism products act as transcriptional regulators in bacteria and yeast, such molecules can serve similar functions in higher organisms (see for example, Tom ins (1975) Science 189: 760-763 and O'Malley (1989) Endocrin? Logy 125: 1119-1120). For example, a biosynthetic pathway in higher eukaryotes is the trajectory of mevalonate leading to the synthesis of cholesterol, bile acids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitamin D, steroid hormones and farnesylated proteins.

FARNESOID X RECEPTOR The farnesoid X receptor (originally isolated as RIP14 (the retinoid X receptor-interlacing protein-14), see for example, Seol et al (1995) Mol.Endocrinol., 9: 72-85) is a member of the Nuclear hormone receptor superfamily and is expressed mainly in the liver, kidney and intestine (see for example, Seol et al., supra and Forman et al (1995) Cell 81: 687-693). This functions as a heterodimer with the retinoid X receptor (RXR) and binds to the response elements in the promoter gene targeting to regulate transcription of the gene. The RXR heterodimers of the farnesoid X receptor bind with a higher affinity for a 1-repeat repeat response element (IR-1), whose consensus of hexamers that bind to the receptor is separated by a nucleotide. The farnesoid X receptor is part of an interrelated process, whose receptor is activated by bile acids (the end product of cholesterol metabolism) (see for example, Makishima et al. (1999) Science 284: 1362-1365, Parks et al. (1999) Science 284: 1365-1368, Wang et al (1999) Mol Cell 3: 543-553), which serve to inhibit cholesterol catabolism See also, Urizar et al. (2000) J. Biol. Chem. 275: 39313-39317.

Nuclear Receptors and Diseases Nuclear receptor activity that includes the farnesoid X receptor and / or orphan nuclear receptor activity has been implicated in a variety of diseases and disorders including, but not limited to, hyperlipidemia and hypercholesterolemia, and complications of including, but not limited to, coronary artery disease, angina pectoris, carotid artery disease, stroke, cerebral arteriosclerosis, and xanthoma, (see, for example, International Patent Application Publication No. WO 00/57915) , osteoporosis and vitamin deficiency (see for example, US Pat. No. 6,316, 5103), hyperlipoproteinemia (see for example, International patent application publication No. WO 01/60818), hypertriglyceridemia, lipodystrophy, peripheral occlusive disease, attack of ischemic stroke, hyperglycemia, and diabetes mellitus (see, for example, Publication of the patent application) and International No. WO 01/82917), disorders related to insulin resistance that include disease status groups, conditions or disorders that constitute "syndrome X" such as glucose intolerance, an increase in triglycerides plasma and a decrease in high density lipoprotein cholesterol concentrations, hypertension, hyperuricemia, small denser low density lipoprotein particles and higher circulating levels of plasminogen activator inhibitor-1, atherosclerosis and gallstones (see for example , International Patent Application Publication No. WO 00/37077), skin and mucous membrane disorders (see for example, U.S. Patent Nos. 6,184,215 and 6,187,814, and International Patent Application Publication No. WO 98 / 32444), obesity, acne (see for example, International patent application publication No. WO 00/49992), and cancer, colestasi s, Parkinson's syndrome and Alzheimer's disease (see for example, International patent application publication No. WO 00/17334). The activity of nuclear receptors, which include the farnesoid X receptor and / or orphan nuclear receptors, has been implicated in physiological processes that include but are not limited to, triglyceride metabolism, catabolism, transport or absorption, metabolism of bile acids, catabolism, transport, absorption, re-absorption or composition of bile concentration, cholesterol metabolism, catabolism, transport, absorption, or reabsorption. Modulation of transcription of cholesterol 7-hydroxylase gene (CYP7A1) (see for example, Chiang et al. (2000) J. Biol. Chem. 275: 10918-10924), HDL metabolism (see for example, Urizar et al., (2000) J. Biol. Chem. 275: 39313-39317), hyperlipidemia, cholestasis, increased cholesterol emanation and increased expression of the cassette transporter protein binding ATP ( ABC1) (see for example, Publication of the international patent application No. WO 00/78972) are also modulated or on the contrary affected by the farnesoid X receptor. Thus, there is a need for compounds, compositions and methods of modulating the activity of nuclear receptors, which include the farnesoid X receptor and / or the orphan nuclear receptors. Such compounds are useful in the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders in which the activity of the receptor is involved.

BRIEF DESCRIPTION OF THE INVENTION Compounds are provided for use in pharmaceutical compositions and methods for modulating the activity of nuclear receptors. In particular, the compounds are provided for use in compositions and methods for modulating the farnesoid X receptor, and / or orphan nuclear receptors. In a modulation, the compounds provided herein are agonists of the farnesoid X receptor. In another embodiment, the compounds provided herein are inverse agonists, partial agonists or partial antagonists of the farnesoid X receptor. Agonists that exhibit reduced efficacy are in certain modalities, antagonists. In a modulation, the compounds for use in the compositions and methods provided herein have the formula (I): (l) or a pharmaceutically acceptable derivative thereof, wherein: X is NR9, 0 or S (0) t (where t is 0 to 2); R30 and R31 are each independently selected from the group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, heterocyclylalkyl optionally substituted, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR32, -SR32, N (R33) R34, -N (R33) S (0) 2R23; -N (R35) N (R35) R34, N (R35) N (R33) S (O) 2R23, -C (0) R3S, -C (0) OR32, -C (S) OR32, -C (0) ) SR32, -C (O) N (R33) R34, C (S) N (R33) R34, -C (0) N (R33) S (0) 2R23, -C (S) N (R33) S ( O) 2R23, C (0) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and C (0) N (R3?) N (R33) S (0) 2R23; or R30 and R3a together with the carbon atoms to which they bind, form an optionally substituted cycloalkyl ring, optionally substituted cycloalkenyl ring, optionally substituted cycloalkynyl ring, optionally substituted heterocyclyl ring, optionally substituted heteroaryl ring or optionally substituted aryl ring with the exception of substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl; R32, R33, R34, R3S and R36 are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R36 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R36 are selected as (a) above, R1 and R2 are each independently selected from a group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl , optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -N (R15) R1G, -N (R15) S (O) 2R23; N (R17) N (R15) R16, -N (R17) N (R1?) S (0) 2R23, -C (0) R18, -C (0) OR14, -C (S) 0R14, -C ( 0) SR14, -C (0) N (R15) R16, -C (O) N (R15) S (O) 2R23, C (O) N (R15) N = R1S, -C (O) N (R17) ) N (R15) R1S and -C (O) N (R17) N (R15) S (O) 2R23; R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl, -C (0) R10, -C ( 0) OR10, -S (0) 2R10, -C (0) N (Ra?) R12, -C (0) N (R11) S (0) 2R23, -C (O) N (R13) N (R11) ) R12, C (0) N (Ra3) N (R11) S (0) 2R23, -N (R13) C (O) R10, -N (R13) C (O) N (R11) R12, -N ( R13) C (0) N (R1: L) S (0) 2R23, -N (R10) C (O) N (R13) N (R11) R12, N (R1?) C (0) N (R13) N (RX1) S (0) 2R23, -N (R13) C (O) OR10, -P (O) OR10 or -P (O) (0R19) 0R12; R4, R5, R6 and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -S (0) 2R14, -N (R15) R16, -N (R15) S (0) 2R23, -C (0) R18, -C (0 ) N (R21) R22, ~ C (0) N (R21) S (0) 2R23; C (0) N (R2) N (R21) R22 and -C (O) N (R24) N (R21) S (O) 2R23; or R4 and R? or Rs and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted heterocyclyl ring, an optionally substituted cycloalkenyl ring or together form a double bond, and the others of R4, R ?, R6 and R7 are as described above; or R6 and R7 together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or R6 and R7, together with the carbon atom to which they are bonded, form an optionally substituted exocyclic double bond, and R4 and R5 are as described above; R9 is hydrogen, optionally substituted alkyl, C (0) R18, -C (0) 0R20 or -S (0) 2R23; R10, Rlx, R12, R13 and R19 are selected as in (a) or (b) as follows: (a) R10, R11, R12, R13 and R19 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R11 and R12 or R12 and R19, together with the atoms to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and the others of R10, R11, R12, R13, and R19, are selected as in (a), above; R14, R15, R16, R17 and R18 are selected as in (a) or (b) as follows: (a) R14, R15, R16, R17 and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R15 and Rls, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R14, R1 ?, Rls, R17 and R18 are selected as in (a) above; R20, R21, R22 and R24 are selected as in (a) or (b) as follows: (a) R20, R21, R22 and R24 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl optionally substituted, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R21 and R22 together with the nitrogen atom to which they bond, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R20, R21, R22 and R24 are selected as in (a) ) above; R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; 0 each of R1-R24 and R31-R36, when substituted, are substituted with one or more substituents, each independently selected from Q1; each of Q1 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl , cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkyl, halosulfonyl, -OR70, -SR70, -R60- C (J) R71, - R60-N (R70) C (J) R71, -0C (0) R71, -R60-N (R75) (R76), -N + (R77) 3, -P (R78) 2, -P (0) ( R78) 2, ~ 0P (0) (R78) 2, -N (R70) S (O) 2R71, -S (0) 2R71, -5 S (0) R82, -OS (0) R83, -OS ( 0) 2R83 or -Si (R83) 3; two groups Q1, whose atoms substituted in a 1,2 or 1,3 configuration, together with the carbon atoms to which they are bonded, form a sicloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; or each Q1 is independently substituted or unsubstituted with one or more substituents each independently selected from Q2; each of Q2 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkyl, halo-sulfonyl, -OR70, -SR70, -R60- C (J) R71, -R60- N (R70) C (J) R71, -OC (0) R71, -R60-N (R75) (R76), -N + (R77) 3, -P (R78) 2, -P (0) (R78) 2, -0P (0) (R78) 2, -N (R70) S (0) 2R71, -S (0) 2R71, - S (0) R82, -0S (0) R83, -0S (0) 2R83 or -Yes (R83) 3; two Q2 groups, which replace atoms in a 1.2 or 1.3 configuration, together with the carbon atoms to which they are bonded form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; each J is independently O, S or -NR70; each R60 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl, -OR72 or -N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are bonded, form a heterocyclyl ring or heteroaryl ring; R75 and R7e are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R7S, together with the nitrogen atom to which they are bonded, form a heterocyclyl ring or heteroaryl ring; each R77 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R78 is alkyl, heteroaryl, heterocyclyl, aryl, -OR79 or -N (R80) R81; R79 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R80 and R81 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R80 and R81, together with the nitrogen atom to which they are bonded, form a heterocyclyl ring or heteroaryl ring; R82 is alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl or -OR83; and each R83 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl. Methods are also provided for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders mediated by, or in which the activity of the nuclear receptor, including the activity of the farnesoid receptor X and / or the orphan nuclear receptor, is involved. , which comprises administering a claimed compound or composition to a subject in need thereof. Such methods include methods of treatment, prevention and improvement of one or more symptoms of hypercholesterolemia, hyperlipoproteine ia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by disturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic shock, conditions, excessive proliferation or disturbed differentiation of the epidermis or mucous membrane, or cardiovascular disorders, using one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof. Methods for modulating the activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, are also provided, using the compounds and compositions provided herein. The compounds and compositions provided herein are active in assays that measure the activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, including the assays provided herein. These methods include inhibiting and over-regulating the activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors. Combination therapy using one or more compounds or compositions provided herein is also contemplated herein., or a pharmaceutically acceptable derivative thereof, in combination with one or more of the following: antihyperlipidemic agents, agents that increase HDL in plasma, anti-hypercholesteroletheric agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin), inhibitors of coenzyme A-acyl: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, (such as anion exchange resins, or quaternary amines (eg cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, fibrizol, vitamin B6 / vitamin B12, antioxidant vitamins, beta blockers , anti-diabetes agents, angiotensin II antagonists, enzyme inhibitors that convert angiotensin, platelet aggregation inhibitors, fibrinogen receptor antagonists, LXR a or β agonists, partial agonists or antagonists, aspirin or fibric acid derivatives. The compound or composition provided herein, or pharmaceutically acceptable derivative thereof, is administered simultaneously with, prior to, or after administration of one or more of the above agents. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided. In the practice of the methods, the effective amounts of the compounds or compositions contain therapeutically effective concentrations of the compounds, which are formulated for systemic administration, including parenteral, oral, or intravenous administration, or for local or topical application for the treatment of the nuclear receptor, including the farnesoid receptor X and / or orphan nuclear receptor, diseases or disorders mediated, or diseases or disorders in which the activity of the nuclear receptor, including the farnesoid receptor X and / or the orphan nuclear receptor activity, is involved, including, but not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, junk immunological disorders, lipid disorders, obesity, conditions characterized by disturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic shock, conditions of excessive proliferation or disturbed differentiation of the epidermis or mucous membrane, or cardiovascular disorders, are administered to an individual who exhibits the symptoms of these diseases or disorders. The amounts are effective to improve or eliminate one or more symptoms of the diseases or disorders. Manufacturing articles containing packaged material, a compound or composition, or a pharmaceutically acceptable derivative thereof, are provided herein, which are effective in modulating the activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, or for the treatment, prevention or reduction of one or more nuclear receptor symptoms, including diseases or disorders mediated by the farnesoid X receptor and / or the orphan nuclear receptor, or diseases or disorders in which the receptor activity Nucleic, including farnesoid receptor X and / or orphan nuclear receptor activity, is involved, within the packaged material, and a label indicating that the compound or composition, or pharmaceutically acceptable derivative thereof, is used to modulate the activity of the nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, or. for the treatment, prevention or reduction of one or more symptoms of the nuclear receptor, including the farnesoid X receptor and / or the orphan nuclear receptor, diseases or disorders mediated, or diseases or disorders in which the activity of the nuclear receptor, including the receptor Farnesoid X and / or nuclear receptor activity is involved.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person ordinary in the art to which this invention pertains. All patents, applications, published requests and other publications are incorporated for reference in their entirety. In the event there is a plurality of definitions for a term in the present, those in this section prevail, unless otherwise stated. As used herein, a nuclear receptor is a member of a superfamily of regulatory proteins that are receptors for, for example, steroids, retinoids, vitamin D, and thyroid hormones. These proteins bind to the elements that act in cis in the promoters of their target genes and modulate the expression of the gene in response to a ligand thereof. Nuclear receptors can be classified based on their DNA binding properties. For example, the glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors are linked as homodimers to hormone-replenishing elements (HREs) or organized as inverted repeats. Another example are receptors, including those activated by retinoic acid, thyroid hormone, vitamin D3, fatty acids / peroxisome proliferators and ecdysone, which bind to HREs as heterodimers with a common pattern, the retinoid receptor X (RXR). Among the last receptors is the farnesoid receptor X. As used herein, an orphan nuclear receptor is a gene product that encompasses the structural characteristics of a nuclear receptor that is identified without any prior knowledge of its association with an assumed ligand and / o for which the natural ligand is unknown. Under this definition, orphan nuclear receptors include, without limitation, farnesoid X receptors, liver X receptors (LXR a and β), retinoid X receptors (RXRa, β and β), and receptors of the proxisome proliferator activator (PPAR OÍ, ß, and?) (see, Giguere, Endocrine Reviews (1999), Vol. 20, No. 5: pp. 689-725).

As used herein, the farnesoid X receptor refers to all mammalian forms of such a receptor including, for example, alternative splicing isoforms and naturally occurring isoforms (see, e.g., Huber et al., Gene. (2002), Vol. 290, pp. 35-43). The farnesoid receptor X representative species include, without limitation, the rat receptor forms (Accession No. to GenBank NMO21745), mouse (GenBank Accession No. NM_009108), and human (GenBank Accession No. NM005123). As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives can be easily prepared by those of ordinary skill in the art using known methods for such derivation. The compounds produced can be administered to animals or humans without substantial toxic effects and either they are pharmaceutically active or they are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, l-para-chlorobenzyl-2-pyrrolidin-1'-methylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkaline earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium acid phosphate and disodium phosphate; and also include, but are not limited to, salts of mineral acids, such as but not limited to chlorohydrates and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, maleates, tartrates, citrates, ascorbates, succinates, butyrates, valerate and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids , sulfonic acids, sulfinic acids and boronic acids. The pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the formula C = C (OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. The pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula C = C (0C (0) R) wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. The pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more molecules of solvent or water, or 1 to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent molecules or Water . As used herein, "treatment" means any manner in which one or more of the symptoms of a disease or disorder are improved or otherwise altered beneficially. The treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating diseases or disorders mediated by the nuclear receptor, or diseases or disorders in which the activity of the nuclear receptor, including the farnesoid X receptor activity or of the orphan nuclear receptor is involved. As used herein, the decrease in the symptoms of a particular disorder by the administration of a particular compound or pharmaceutical composition refers to any decrease, whether permanent or temporary, final or transient that can be attributed to, or associated with, administration of, the composition. As used herein, "IC50" refers to an amount, concentration, or dose of a particular test compound that achieves a 50% inhibition of the maximum response, such as modulation of the activity, of the nuclear receptor, including the receptor. Farnesoid X, in the test that measures such response. As used herein, "EC50" refers to a dose, concentration or amount of a particular test compound that externalizes a dose-dependent response to 50% of the maximum expression of a particular response that is induced, evoked or potentiated. by the particular test compound. • As used herein, a prodrug is a compound that, during in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug can be designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the taste of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of the pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). "When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include geometric isomers of both E and Z. Similarly, all tautomeric forms are also They intend to be included.; It will be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either (R) or (S) configuration, or may be a mixture thereof. In this manner, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, such residues can be of either the L or D form. The configuration for naturally occurring amino acid residues is generally L. When not specified, the residue is the L form. used herein, the term "amino acid" refers to amino acids which are racemic, or either of D or L configuration. The designation "d" which precedes the designation of an amino acid (for example, dAla, dSer, dVal, etc.) refers to the D isomer of the amino acid. The designation "dl" precedes the designation of an amino acid (eg, dlPip) refers to the mixture of the amino acid L and D isomers It will be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of ordinary skill in the art will recognize that the administration of a compound in its (R) form is equivalent, for compounds undergoing in vivo epimerization, to the administration of the compounds in their (S) form. optically active (+) and (-), (R) 'and (S), or (D) and (L) can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. As used herein, substantially pure means sufficiently homogeneous to appear free of easily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (CCD), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectroscopy (EM), used by those of ordinary skill in the art to evaluate such purity, or sufficiently pure in such a way that further purification may not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.

Methods for purifying the compounds to produce substantially chemically pure compounds are known to those skilled in the art. A chemically substantially pure compound can, however, be a mixture of stereoisomers. In such cases, further purification may increase the specific activity of the compound. As used herein, the alkyl, alkenyl, and alkynyl carbon chains are not specified, contain from 1 to 20 carbons, or 1 or 2 to 16 carbons, and are straight or branched. Alkenyl carbon chains of from 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds and carbon alkenyl chain of 2 to 16 carbons, in certain embodiments, they contain 1 to 5 double bonds. The chains of 'alkynyl carbon from 2 to 20 carbons, in certain embodiments, contain 1 to 8 triple bonds, and alkynyl carbon chain of 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds. Exemplary alkyl, alkenyl and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, allyl (propenyl) and propargyl (propinyl). As used herein, lower alkyl, lower alkenyl, and lower alkynyl refers to carbon chains having from about 1 or about 2 carbons to about 6 carbons. As used herein, "alk (en) (in) yl" refers to an alkyl group containing at least one double bond and at least one triple bond. As used herein, "cycloalkyl" refers to saturated or monocyclic ring systems, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; Cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. The cycloalkenyl and cycloalkynyl groups can, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenyl groups, in further embodiments, containing 4 to 7 carbon atoms and cycloalkynyl groups, in additional embodiments, containing 8 to 10 carbon atoms. carbon. The ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of a ring or two or more rings which may be joined together in a fused, bridged or spiro-connected manner. "Cycloalk (en) (in) yl" refers to a cycloalkyl group that contains at least one double bond and at least one triple bond. As used herein, "aryl" refers to monocyclic or multicyclic aromatic groups containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as substituted or unsubstituted fluorenyl, substituted or unsubstituted phenyl, and substituted or unsubstituted naphthyl. As used herein, "heteroaryl" refers to monocyclic or aromatic multicyclic ring systems, in certain embodiments, from about 5 to about 15 members where one or more, in a 1 to 3 mode, of the The ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur. The heteroaryl group can optionally be fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl., quinolinyl and isoquinolinyl. As used herein, a "heteroaryl" group is a heteroaryl group that is positively charged to one or more of the heteroatoms. As used herein, "heterocyclyl" refers to a stable 3- to 18-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclyl radical may be partially or fully saturated, or aromatic. Examples of such heterocyclyl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzolyl, benzothiadiazolyl, benzonaphtofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl. (benzothiophenyl), benzotriazolyl, benzo [4, 6] imidazo [1,2-a] pyridinyl; carbazolyl, cinnolinyl, dioxolanyl, dibenzofuranyl, decahydroisoquinolyl, furanyl, furanonyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, indazolyl, isoindolyl, indole-inyl, isoindolinyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, octahydroindolyl, Octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, "triazinyl, tetrahydropyranyl, thiophenyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. As it is used in l to present, "oxacyclohexyl" refers to a cyclohexyl ring wherein a carbon in the ring is replaced by an oxygen, for example tetrahydropyranyl. As used herein, "dioxacyclohexyl" refers to a cyclohexyl ring wherein 2 carbons in the ring are replaced by two oxygen atoms, one example of which is teratohydrodioxanil. As used herein, "azacyclohexyl" refers to a cyclohexyl ring wherein a carbon in the ring is replaced by a nitrogen, for example tetrahydropiperidinyl. As used herein, "diazacyclohexyl" refers to a cyclohexyl ring wherein two carbons in the ring are replaced by two nitrogen atoms, one example of which is piperazinyl. As used herein, "oxa-azacyclohexyl" refers to a cyclohexyl ring wherein two carbons in the ring are replaced by a nitrogen atom and an oxygen atom, two examples of such are morpholinyl or oxazinyl. As used herein, "thia-azacyclohexyl" refers to a cyclohexyl ring wherein two carbons in the ring are replaced by a nitrogen atom and an oxygen atom, an example of such is thiazinyl. As used herein, "tia cyclohexyl" refers to a cyclohexyl ring wherein a carbon in the ring is replaced by a sulfur atom, an example of which is tetrahydrothiopyranyl. How it is used herein, "dithiacyclohexyl" refers to a cyclohexyl ring in which two carbons in the ring are replaced by two sulfur atoms. As used herein, "aralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by an aryl group. As used herein, "heteroaralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group. As used herein, "halo", "halogen" or "halide" refers to F, Cl, Br or I. As used herein, pseudohalide or pseudohalo groups are groups that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides. The pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, and azide.

As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms is replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and l-chloro-2-fluoroethyl. As used herein, "haloalkoxy" refers to RO- in which R is a haloalkyl group. As used herein, "sulfinyl" or "thionyl" refers to -S (O) -. As used herein, "sulfonyl" or "sulfuryl" refers to -S (0) 2-. As used herein, "sulfo" refers to -S (0) 20-. As used herein, "halosulfonyl" refers to -S (0) 2 -R in which R is a halo group, preferably fluoro. As used herein, "carboxy" refers to a divalent radical, -C (0) 0-. As used herein, "carbamoyl" or "aminocarbonyl" refers to -C (0) NH2. As used herein, "alkylaminocarbonyl" refers to -C (0) NHR in which R is alkyl, including lower alkyl. As used herein, "dialkylaminocarbonyl" refers to -C (0) NR'R in which R 'and R are independently alkyl, including lower alkyl; "carboxamide" refers to groups of the formula -NR'COR in which R 'and R are independently alkyl, including lower alkyl. As used herein, "diarylaminocarbonyl" refers to -C (0) NRR 'in which R and R' are independently selected from aryl, including lower aryl, such as phenyl. As used herein, "arylalkylaminocarbonyl" refers to -C (0) NRR 'in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R 'is alkyl , including lower alkyl. As used herein, "arylaminocarbonyl" refers to -C (0) NHR in which R is aryl, including lower aryl, such as phenyl. As used herein, "hydroxycarbonyl" refers to -COOH. As used herein, "alkoxycarbonyl" refers to -C (0) 0R wherein R is alkyl, including lower alkyl. As used herein, "aryloxycarbonyl" refers to -C (0) 0R in which R is aryl, including lower aryl, such as phenyl. As used herein, "alkoxy" and alkylthio "refer to RO- and RS-, in which R is alkyl, including lower alkyl." As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, in which R is aryl, including lower aryl, such as phenyl As used herein, "alkylene" refers to a linear, branched or cyclic hydrocarbon group, in certain linear or branched embodiments , aliphatic divalent, in one embodiment has from 1 to about 20 carbon atoms, in another embodiment it has from 1 to 12 carbons In a further embodiment, alkylene includes lower alkylene Optionally, one or more alkylene groups may be inserted throughout the alkylene group. oxygen atoms, sulfur, including optionally substituted S (O) and S (0) 2 / or nitrogen groups, including -NR- and -N + RR- groups, where the nitrogen substituents are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or COR ', where R' is alkyl, aryl, aralkyl, heteroaryl or, heteroaralkyl, -OY or -NYY, wherein Y is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH-), propylene (- (CH2) 3 ~), methylenedioxy (-0-CH2-0-) and ethylenedioxy (-0- (CH2) 2-0-). The term "lower alkylene" refers to alkylene groups having 1 to 6 carbons. In certain embodiments, the alkylene groups are lower alkylene, including alkylene of 1 to 3 carbon atoms. As used herein, "azaalkylene" refers to - (CRR) n-NR- (CRR) m-, where n and m are each independently an integer from 0 to 4. As used herein, "oxaalkylene" refers to - (CRR) n-0- (CRR) m-, where n and m are each independently an integer from 0 to 4. As used herein, "thiaalkylene" refers to - (CRR) nS- ( CRR) m-, - (CRR) aS (O) - (CRR) m-, y- (CRR) nS (O) 2- (CRR) m ~, where n and m are each independently an integer from 0 to 4. As used herein, "alkenylene" refers to a divalent, straight, branched or cyclic aliphatic hydrocarbon group, in a straight or branched embodiment, in certain embodiments having from 2 to about 20 carbon atoms. and at least one double bond, in other modalities 1 to 12 carbons. In further embodiments, the alkenylene groups include lower alkenylene. Optionally, one or more oxygen, sulfur or nitrogen atoms optionally substituted may be inserted along the alkenylene group, where the nitrogen substituent is alkyl. Alkenylene groups include, but are not limited to, CH = CH-CH = CH- and -CH = CH-CH2-. The term "lower alkenylene" refers to alkenylene groups having 2 to 6 carbons. In certain embodiments, the algenylene groups are lower alkenylene, including alkenylene of 3 to 4 carbon atoms. As used herein, "alkynylene" refers to a divalent, straight, branched or cyclic aliphatic hydrocarbon group, in certain straight or branched embodiments, in a mode having from 2 to about 20 carbon atoms and at least one triple bond, in another modality 1 to 12 carbons. In a further embodiment, alkynylene includes lower alkynylene. Optionally, one or more oxygen, sulfur or optionally substituted nitrogen atoms may be optionally inserted along the alkynylene group, where the nitrogen substituent is alkyl. Alkynylene groups include, but are not limited to, -C = C-C = C-, -C = C- and -C = C-CH2 ~. The term "lower alkynylene" refers to alkynylene groups having 2 to 6 carbons. In certain embodiments, the alkynylene groups are lower alkynylene, including alkynylene of 3 to 4 carbon atoms. As used herein, "alk (en) (in) ylene" refers to a divalent, straight, branched or cyclic aliphatic hydrocarbon group, in certain straight or branched embodiments, in a mode having from 2 to about 20 carbon atoms and at least one triple bond, and at least one double bond; in another mode 1 to 12 carbons. In additional modalities, alq (en) (in) ileno includes alq (en) (in) inferior ileno. Optionally, one or more oxygen, sulfur or nitrogen atoms optionally substituted may be inserted along the alkynylene group, where the nitrogen substituent is alkyl. The groups alq (en) (in) ileno include, but are not limited to, -C = C- (CH2) nC = C-, where n is 1 or 2. The term "alq (en) (in) ileno inferior "refers to groups alq (en) (in) ileno that have up to 6 carbons. In certain embodiments, groups alq (en) (in) ileno have about 4 carbon atoms. As used herein, "cycloalkylene" refers to a saturated divalent mono or ulti cyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments 3 to 6 carbon atoms; Cycloalkenylene and cycloalkynylene refer to divalent mono- or multicyclic ring systems which include at least one double bond and at least one triple bond. The cycloalkenylene and cycloalkynylene groups can, in certain embodiments, contain 3 to 10 carbon atoms, with groups cycloalkenylene in certain embodiments containing 4 to 7 carbon atoms and cycloalkynylene groups in certain embodiments containing 8 to 10 carbon atoms. Ring systems of cycloalkylene groups, cycloalkenylene and cycloalkynylene can be composed of one ring or two or more rings that can be attached in. set in a merged, bridged or spiro way. "Cycloalk (en) (in) ylene" refers to a cycloalkylene group containing at least one double bond and at least one triple bond. As used herein, "arylene" refers to a divalent, cyclic or polycyclic aromatic group, in certain monocyclic moieties, in a moiety having from 5 to about 20 carbon atoms and at least one aromatic ring, in another mode 5 to 12 carbons. In additional embodiments, arylene includes lower arylene. Arylene groups include, but are not limited to, 1,2-, 1,3- and 1,4-phenylene. The term "lower arylene" refers to arylene groups having 6 carbons. As used herein, "heteroarylene" refers to a monocyclic or multicyclic divalent aromatic ring system, in a mode of about 5 to about 15 ring atoms, where one or more, in certain embodiments 1 through 3 , of the atoms in the ring system is a heteroatom, that is, an element other than carbon, which includes but is not limited to, nitrogen, oxygen or sulfur. The term "lower heteroarylene" refers to heteroarylene groups having 5 or 6 ring atoms. As used herein, "heterocyclylene" refers to a monocyclic or multicyclic divalent nonaromatic ring system, in certain 3 to 10 member modalities, in a 4 to 7 member modality, in another 5 to 6 member modality, where one or more, including 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.

As used herein, "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted cycloalkyl", "substituted cycloalkenyl" "substituted cycloalkynyl" "substituted aryl", "substituted heteroaryl", "substituted heterocyclyl", "substituted alkylene", "substituted alkenylene", "substituted alkynylene", "substituted cycloalkylene", "substituted cycloalkenylene", "substituted cycloalkynylene", "substituted arylene", "substituted heteroarylene" and "substituted heterocyclylene" refer to alkyl groups, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl ,. heteroaryl, heterocyclyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, arylene, heteroarylene and heterocyclylene, respectively, which are substituted with one or more substituents, in certain embodiments one, two, three or four substituents, wherein the substituents are is defined in the present, in one modality they are selected from Q1. As used herein, "alkylidene" refers to a divalent group, such as = CR'R ", which is linked to an atom of another group, forming a double bond. The alkylidene groups include, but are not limited to, methylidene (= CH) and ethylidene (= CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group in which either R 'or R "is an aryl group The" cycloalkylidene "groups are those where R" and R "are linked to form a ring The "heterocyclylidene" groups are those in which at least one of R 'and R "contain a heteroatom in the chain, and R' and R" are linked to form a heterocyclic ring. present, "amido" refers to the divalent group -C (0) NH- "Thioamido" refers to the divalent group -C (S) NH- "Oxamido" refers to the divalent group -OC (0) NH ~. "Thiaamido" refers to the divalent group -SC (0) NH-. "'Dithiaamido" refers to the divalent group -SC (S) NH- "Ureido" refers to the divalent group -HNC (0) NH-. "Thioureido" refers to the divalent group -HNC (S) NH-, As used herein, "semicarbazide" refers to -NHC (O) NHNH- "Carbazate" refers to the divalent group - OC (0) NHNH- "Isothiocarbazate" refers to the divalent group - SC (0) NHNH-. "Tiocarbaz ato "refers to the divalent group - 0C (S) NHNH-. "Sulfonylhydrazide" refers to the divalent group -S02NHNH-. "Hydrazide" refers to the divalent group C (0) NHNH ~. "Azo" refers to the divalent group -N = N-. "Hydrazinyl" refers to the divalent group -NH-NH-. Where the number of any given substituent is not specified (eg, haloalkyl), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogen. As in the other example, "C 1 -3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three carbons. As used herein, abbreviations for any protecting group, amino acids and other compounds are, unless otherwise indicated, in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see (1972) Biochem 11: 942-944). As used herein, the following terms have their meaning accepted in the chemical literature. AcOH acetic acid CDl carbodiimide CHC13 chloroform Conc concentrated DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene DCM. dichloromethane DDQ 2, 3-dichloro-5,6-dicyan-1,4-benzoquninone DIEA diisopropyl ethylamine DMAP 4- (dimethylamino) iridine DME 1,2-dimethoxyethane DMF N, -dimethylformamide DMSO dimethisulfoxide ELSD light scattered detector evaporator - EtOAc ethyl acetate EtOH ethanol (100%) Et20 diethyl ether HBTU hexafluorophosphate 1-H-Benzotriazolium, 1- [bis (dimethylamino) methylene] -hexafluorophosphate (1-), 3-oxide O- (Benzotriazol-1-yl) - N, N, N ', N' tetramethyluronium Hex hexanes H2S04 sulfuric acid LDA di (iso-propyl) lithium amide MeCN acetonitrile MeOH methanol NaBH3CN sodium cyanoborohydride Pd / C palladium on activated carbon TEA triethylamine THF tetrahydrofuran TFA trifluoroacetic acid B. Preferred Modes of the Compounds of the Invention Compounds are provided for use in compositions and methods for modulating the activity of nuclear receptors.

In particular, compounds are provided for use in compositions and methods for modulating the farnesoid X receptor and / or orphan nuclear receptors. In certain embodiments, the compounds of the invention, as described above in the Brief Description of the Invention, are compounds of the formula (I) where: X is NR9, 0, or S (0) (where t is 0 to 2); And it is CR30 or N; Z is CR31 or N; wherein R30 and R31 are independently selected from the), Ib), le), ld), le), lf) and lg); R1 is independently selected from 2a), 2b), 2c), 2d), 2e), 2f), 2g), 2h), 2i), 2j) 2k) and I); R2 is independently selected from 3a), 3b), 3c), 3d), 3e), 3f), 3g), 3h), 3i) and 3j); R3 is independently selected from 4a), 4b), 4c), 4d), 4e), 4f), 4g), 4h), 4i), 4j), 4k), 41), 4m), 4n), 4o), 4p) and 4q); R9 when presented is independently selected from 5a), 5b), 5c) and 5d); R4, Rs, Rs and R7 are each independently selected from 6a) -6y). la) R30 and R31 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted cycloalkenyl ring, optionally substituted cycloalkynyl ring, optionally substituted heterocyclyl ring, optionally substituted heteroaryl ring or aryl ring optionally substituted with the exception of substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl; Ib) R30 and R31 together with the carbon atoms to which they bind, form an optionally substituted cycloalkyl ring, optionally substituted cycloalkenyl ring, cycloalkynyl ring < optionally substituted, optionally substituted heterocyclyl ring, optionally substituted heteroaryl ring or optionally substituted aryl ring, with the proviso that, however, aryl is not phenyl or naphthyl; le) R30 and R31 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted cycloalkenyl ring, optionally substituted cycloalkynyl ring, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; Id) wherein the cycloalkyl ring, the cycloalkenyl ring, the cycloalkynyl ring, the heterocyclyl ring, the heteroaryl ring in le), when substituted, is substituted with substituents selected from the group consisting of halo, pseudohalo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halosulfonyl, nitro, -OR70, -SR70, -R60-C (= J) R71, -R60 ~ N (R70) C (O) R71, -OC (0) R71, -R60-N (R75) (R76), -N (R70) S (O) 2R71 and -S (0) 2R71; each Rβ0 is independently a direct bond or alkylene, - each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or 'heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl, -OR72 or ~ N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are bonded, form a heterocyclic ring or heteroaryl ring; and R7S and R76 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R7? and R7S, together with the nitrogen atom to which they are bonded, form a heterocyclyl ring or heteroaryl ring; le) R30 and R31 together with the carbon atoms to which they bind, form a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; and lf) R30 and R31 together with the carbon atoms to which they bind, form pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, oxacyclohexyl,, oxacyclohexyl, dioxacyclohexyl, azacyclohexyl, diazacyclohexyl, oxa-azacyclohexyl, thia-azacyclohexyl, cyclohexyl, or dithiacyclohexyl; and lg) R30 and R31 together with the carbon atoms to which they are bonded, is pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl or 1,2,4-triazinyl; wherein R1 is selected from 2a), 2b), 2c), 2d), 2e), 2f), 2g), 2h), 2i), 2j) 2k) and 1): 2a) R1 is optionally substituted alkyl, aryl optionally substituted, optionally substituted heteroaryl, -C (0) R18, -C (0) 0R14, -C (O) N (R15) R16, or C (0) N (R17) N (R1B) R16; where R14, R15, R15, R17 and R18 are each as defined above in the Brief Description of the Invention; and X, Y, Z, R2-R7 and R9 are each as defined above in the Brief Description of the Invention; 2b) R1 is independently selected from halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -N (R15) R15, N (R15) S (0) 2R23; -N (R17) N (R15) R16, -N (R17) N (R15) S (O) 2R23, -C (0) R18, -C (0) OR14, -C (S) OR14, -C ( 0) SR14, -C (O) N (R15) R16, C (0) N (R15) S (0) 2R23, -C (0) N (R15) N = R16, -C (0) N (R17) ) N (R15) R16 and -C (0) N (R17) N (R15) S (0) 2R23, wherein R14, R15, R16, R17 and R18 are selected as described above in the Brief Description of the Invention 2c R1 is optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -N (R15) R16, -N (R17) N (R15) R16, -C (0) R18, -C (0) 0R14, -C (0) N (R15) R16,. or -C (O) N (R17) N (R1?) R16; wherein R14, R15, R16, R17 and R18 are as described above in the Brief Description of the Invention; 2d) R1 is -OR14, -SR14, -N (R15) R16, -N (R15) S (0) 2R23; -N (R17) N (R15) R16, -N (R17) N (R15) S (0) 2R23, -C (0) R18, -C (0) 0R14, -C (S) 0R14, -C ( 0) SR14, -C (0) N (R15) R16, -C (0) N (R15) S (O) 2R23, C (O) N (R15) N = R16, -C (O) N (R17) ) N (R15) R16 or -C (O) N (R17) N (R15) S (0) 2R23; 2e) R1 is -C (0) R18, -C (0) OR14, -C (S) 0R14, -C (0) SR14, C (0) N (R15) R16, -C (0) N (R1) ?) S (0) 2R23, -C (O) N (R15) N = R16, C (0) N (R17) N (R15) R16 or -C (0) N (R17) N (R15) S ( 0) 2R23; 2f) R1 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, -C (0) R18, -C (0) 0R14-, C (0) N (R17) NRlsR16 or -C (0) N (R15) Rls; 2g) R18 in 2e) is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted aralkyl and R15 and R16 are as described above in the Brief Description of the Invention; 2h) R15 in 2e) is optionally substituted alkyl or optionally substituted cycloalkyl; 2i) R15 in 2e) is alkyl or cycloalkyl and R16 is hydrogen; 2j) R1 is selected from -C (0) R18, -C (0) 0R14, C (0) N (R17) NR15R16 or -C (0) N (R15) R16 where R14, R15 and R16 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl and R18 is optionally substituted alkyl; 2k) R1 is -C (0) OCH2CH3, -C (0) OCH3 / -C (O) OCH (CH3) 2, -C (0) 0H, -C (0) OCH2CH2CH3, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl , cyclopentylaminocarbonyl, 2-butylaminocarbonyl, or cyclopropyl methylaminocarbonyl; and 21) R1 is -C (0) 0R14, -C (0) N (R15) R1 and R14, R15 and R16 are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; wherein R2 is selected from 3a), 3b), 3c), 3d), 3e), 3f), 3g), 3h), 3i) and 3j): 3a) R 2 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, - (CO) O- (optionally substituted alkyl), -C (0) OH, or -C (O) N (R1?) R16, wherein R15 and R16 are as described above in the Brief Description of the invention; 3b) R15 in 3a) is optionally substituted alkyl; and 3c) R15 in 3a) is alkyl and R16 is hydrogen; 3d) R 2 is -C (0) OCH 2 CH 3, -C (0) OCH 3, -C (O) OCH (CH 3) 2, -C (0) 0H, -C (0) OCH 2 CH 2 CH 3, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, cyclopropylaminocarbonyl , cyclopentylaminocarbonyl, 2-butylaminocarbonyl, or cyclopropyl methylaminocarbonyl. 3e) R2 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 3f) R2 is hydrogen, halo or optionally substituted alkyl. In another modality; 3g) R2, when substituted, is substituted with halo, pseudohalo, alkyl, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, alkoxycarbonyl, aryl, halosulfonyl ,. or haloalkoxy; 3h) R2 is hydrogen or alkyl; 3i) R2 is hydrogen; and 3j) R 2 is independently selected from halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR 14 , -SR14, -N (R15) R? E, -N (R15) S (0) 2R23; N (R17) N (R15) R16, -N (R17) N (R15) S (0) 2R23, -C (0) R18, -C (0) 0R14, C (S) 0R14, -C (0) SR14, -C (0) N (R15) R1S, -C (0) N (R1?) S (O) 2R23, C (0) N '(R15) N = R16, -C (0) N (R17) ) N (R15) R1 & and -C (O) N (R17) N (R15) S (0) 2R23, wherein R14, R15, R16, R17 and R18 are selected as described above in the Brief Description of the Invention; where R3 is selected from 4a), 4b), 4c), 4d), 4e), 4f), 4g), 4h), 4i), 4j), 4k), 41), 4m), 4n), 4o) , 4p) and 4q): 4a) R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl, -C (0) R10, - C (0) 0R10, -S (0) 2R10, -C (0) N (Rlx) R12, -C (0) N (R? A) S (0) 2R23, -C (O) N (R13) N (R11) R12, C (0) N (R13) N (RX1) S (0) 2R23, -C (R13) C (0) R10, -N (R13) C (O) N (R11) R12, - N (R13) C (0) N (R1: L) S (0) 2R23, -N (R10) C (O) N (R13) N (R11) R12, N (R10) C (O) N ( R13) N (R11) S (O) 2R23, -N (R13) C (0) OR10, -P (0) 0R10 or - P (0) (0R19) 0R12, where R10, R11, R12,, R13, R19 and R19 are as described in the Brief Description of the Invention; 4b) R3 is -C (0) R10, -C (0) 0R10, -S (O) 2R10; -C (0) N (R11) R12, - C (0) N (Ru) S (0) 2 23, -C (0) N (R13) N (R1X) R12, - C (0) N (R13) ) N (Ru) S (0) 2R23, -N (R13) C (O) R10, -N (R13) C (O) N (R11) R12, - N (R13) C (0) N (R11) S (0) 2R23, -N (R10) C (0) N (R13) N (R11) R12, N (R10) C (O) N (R13) N (R11) S (O) 2R23, -N ( R13) C (0) OR10, -P (0) 0R10 or - P (0) (0R1) 0R12; 4c) R3 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -C (0) R10, -C ( 0) 0R10, -S02R10, C (0) N (RX1) R12, -C (0) N (R13) N (Rxx) R12, -N (R13) C (0) RX0, N (RX3) C (0 ) N (R1X) RX2, -N (RXO) C (0) N (R13) N (R1X) R12, -N (R13) C (0) OR10, - P (0) OR10, or -P (0) (OR19) OR12; wherein R10, R11, R12, R13 and R19 are selected as described in the Brief Description of the • Invention; 4d) R3 is hydrogen, -C (0) R10, -C (0) OR10, -S (0) 2R10 or -C (0) N (R1X) R12; wherein R10, R11 and R12 are as described in the Brief Description of the Invention; 4e) R10 in 4d) is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, or optionally substituted aralkyl; 4e) R10 in 4e), when substituted, is substituted with halo, pseudohalo, alkyl, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, halosulfonyl, aryl, or -C (0) 0R72, where R72 is alkyl. In another embodiment, R 11 and R 12 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heheterocyclyl; or R11 and R12 together with the atoms to which they bind, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; 4f) R11 in 4d) is hydrogen, or optionally substituted alkyl; 4g) R11 in 4d) is hydrogen or alkyl; 4h) R11 in 4d) is hydrogen; 4i) R3 is -C (0) - (optionally substituted aryl), C (0) - (optionally substituted heteroaryl), -C (0) - (optionally substituted alkyl), hydrogen, -S02- (optionally substituted aryl) - , -C (O) (CH2) r- (optionally substituted aryl) where r is an integer of 1-4, -C (0) O- (optionally substituted aryl), or -C (O) N (H) - (optionally substituted aryl). 4j) R3 is -C (O) - (optionally substituted aryl) where the substituents when present are halo, pseudohalo, alkyl, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, -C (0) O-alkyl, aryl or - S02F. In another embodiment, R3 is -C (0) ~ heteroaryl; 4k) R3 is -C (O) -alkyl; 41) R3 is hydrogen; 4m) R3 is -S02- (optionally substituted aryl), wherein the substituents when present are alkyl, halo, alkoxy or haloalkoxy; 4n) R3 is -C (O) - (CH2) r-aryl where r is 1 or 2; 4o) R3 is -C (O) -O- (optionally substituted aryl), wherein the substituents when present are halo, alkoxy or alkyl; 4p) R3 is -C (0) N (H) - (optionally substituted aryl), wherein the substituents when present are halo, alkoxy or alkyl; and 4q) R3 is selected from hydrogen, -C (0) - (4-chlorophenyl), -C (0) - (4-fluorophenyl), -C (0) - (2-furyl), C (0) - (2,4-dichlorophenyl), -C (0) - (3-nitrophenyl), -C (0) - (phenyl), -C (0) - (methyl), -C (0) - (4-tert -butylphenyl), -S02- (4-methylphenyl), '-S02- (4-tert-butylphenyl), -C (0) - (2-methoxyphenyl), -C (O) - (3-methoxyphenyl), - C (0) - (4-methoxyphenyl), -C (O) - (benzyl), -C (O) O -phenyl, -C (0) 0- (4-chlorophenyl), -C (0) 0- (4-methoxyphenyl), -C (0) 0- (4-methylphenyl), -C (O) N (H) -phenyl, -C (0) N (H) - (4-chlorophenyl), -C ( 0) N (H) - (2,4-dichlorophenyl), -C (0) N (H) - (4-methoxyphenyl), C (0) N (H) - (4-methylphenyl), -C (0 ) - (3, 4-methylenedioxyphenyl), C (0) -n-octyl, -C (0) -CH2CH2phenyl, -S02- (4-chloro-phenyl), -S02- (4-methoxyphenyl), -S02- (3 , 4-dimethoxyphenyl), -S02- (4-trifluoromethoxyphenyl), -C (0) - (2,3-difluorophenyl), -C (0) - (2,4-difluorophenyl), -C (0) - ( 2, 5-difluorophenyl), -C (0) - (2,6-difluorophenyl), -C (0) - (3,4-difluorophenyl), -C (0) - (3,5-di) fluorophenyl), -C (0) - (2, 3, 4-trifluorophenyl), -C (0) - (2, 3, 6-trifluorophenyl), -C (0) - (2,4,5-trifluorophenyl) , -C (0) - (2,3,4,5-tetrafluorophenyl), -C (0) - (2, 3, 4, 5, 6-pentafluorophenyl), -C (0) - (2, 5- bis (trifluoromethyl) phenyl), C (0) - (3,5-bis (trifluoromethyl) -phenyl), -C (O) - (2-trifluoromethylphenyl), -C (0) - (3-trifluoromethylphenyl), -C (0) - (4 -trifluoromethylphenyl), -C (0) - (2-fluorophenyl), -C (0) - (3-fluorophenyl), -C (0) - (4-nitrophenyl), -C (0) - (3-nitro) -4-methylphenyl), -C (0) - (4-methoxycarbonylphenyl), -C (0) - (3-pyridyl), -C (0) - (4-pyridyl), -C (0) - (3 -cyanophenyl), -C (0) - (3,4-dimethoxyphenyl), -C (0) - (2-methylphenyl), -C (0) - (4-methylphenyl), -C (0) - (2 -chlorophenyl), -C (0) - (2-naphthyl), C (0) - (4-biphenyl), -C (0) - (4-fluorosulfonylphenyl), -C (0) - (3-methylphenyl) , and -C (O) - (3-chlorophenyl); wherein R9 is selected from 5a), 5b), 5c) and 5d) 5a) R9 is hydrogen or optionally substituted alkyl; 5b) R9 is optionally substituted alkyl which, when substituted, is substituted with halo, pseudohalo, alkyl, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, alkoxycarbonyl, aryl, halosulfonyl, or haloalkoxy; 5c) In another embodiment, R9 is hydrogen, optionally substituted alkyl, or -S (0) 2R43; wherein R43 is as defined in the Brief Description of the Invention; and 5d) R9 is hydrogen; wherein R4, R5, Rs and R7 are each independently selected from 6a) -6y): 6a) R4, R5, R6 and R7 are each independently selected from a group consisting of -hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -S (0) 2R14, -N (R15) R16, - N (R15) S (0) 2R23, -N (R15) C (0) R23, -C (0) R18, -C (0) 0R20, C (0) N (R21) R22, -C (0) N (R21) S (0) 2R23; -C (O) N (R24) N (R21) R22 and C (0) N (R24) N (R21) S (0) 2R23 where R14, R1S, Rls, R17, R20, R21, R22, R23 and R24 are as described in the Brief Description of the Invention; 6b) R4, R5, R6 and R7 are independently selected from hydrogen, halo, optionally substituted alkyl, C (0) OH, -C (O) O-alkyl, or -C (O) N (R21) R22; wherein R21 and R22 are each independently hydrogen, optionally substituted alkyl, or together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic or heteroaryl ring. 6c) R4, R5, Re and R7 are independently selected from hydrogen, halo, optionally substituted alkyl, C; (O) 0H, -C (O) -O-alkyl, or -C (O) N (R21) R22; wherein R21 and R22 are each independently hydrogen or alkyl, or together with the nitrogen atom to which they are attached, form a heterocyclic ring. 6d) R4, R5, R6 and R7 are independently selected from hydrogen, halo, methyl, ethyl, -C (0) 0H, -C (0) OCH2CH3, -C (0) -N (H) CH2CH3 / -C ( 0) -piperidin-1-yl, or -CH20C (0) - (4-fluorophenyl). 6e) R4 and R5 or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, an optionally substituted cycloalkenyl ring, or together form a double bond and the others of R4, Rs , R6 and R7 are as described above; or Rs and R7, together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted exocyclic double bond, and R4 and R5 are as described above; 6f) R4 and R5 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted cycloalkenyl and R6 and R7 together with the carbon atom to which they are bonded, form an optionally substituted cycloalkyl or optionally substituted cycloalkenyl; 6g) R4, R5, Rs and R7 are each independently hydrogen, halo or optionally substituted alkyl; 6h) R4, R5, R6 and R7 are each optionally substituted alkyl; 6i) R4 and R5 are each hydrogen - or optionally substituted alkyl and R6 and R7 are each optionally substituted alkyl; 6j) R4 and R5 are each hydrogen and R6 and R7 are each optionally substituted alkyl; 6k) In another embodiment, R6 and R7 are each independently hydrogen or optionally substituted alkyl and R4 and Rs are each optionally substituted alkyl; 61) R6 and R7 are each hydrogen and R4 and R5 are each optionally substituted alkyl; 6m) R4 and R5 are each hydrogen or optionally substituted alkyl and R6 and R7 together with the carbon atom to which they bind, form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl, -6n) R4 and R? each is hydrogen and Rs and R7 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl; 6o) R and R are each optionally substituted alkyl and R6 and R7 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl; 6p) R6 and R7 are each hydrogen or optionally substituted alkyl and R4 and R5 together with the -carbon atom to which they are attached, form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl; 6q) R6 and R7 are each hydrogen and R4 and R5 together with the carbon atom to which they bond, form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl; 6r) Rs and R7 are each optionally substituted alkyl and R4 and R5 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl; 6s) R4 and R5 are optionally substituted alkyl, or R4 and R5 together with the carbon atom to which they are attached, form cycloalkyl, and R6 and R7 are each hydrogen; 6t) R4 and R5 are hydrogen and R6 and R7 are each optionally substituted alkyl, or R6 and R7 together with the carbon atom to which they are attached, independently form an optionally substituted cycloalkyl ring, optionally substituted heterocyclyl, optionally substituted cycloalkenyl, or Rs and R7, together form an optionally substituted imino, optionally substituted thioxo, optionally substituted oxo, optionally substituted oxime or an optionally substituted hydrazone; or R6 and R7 together with the carbon atom to which they bind, form an endocyclic bond or an optionally substituted exocyclic double bond; 6u) R4 and R5 are hydrogen and R6 and R7 are each optionally substituted lower alkyl or R6 and R7 together with the carbon atom to which they are linked form cycloalkyl; 6v) R4 is hydrogen, optionally substituted alkyl, -C (0) OR20 or -C (0) N (R21) R22, wherein R20 is hydrogen, alkyl and R21 and R22 are each independently hydrogen, optionally substituted alkyl, or together with the nitrogen atom to which they bind, they form an optionally substituted heterocyclyl ring or a heteroaryl ring. In another embodiment, R4, R20, R, and R22, when substituted, are independently substituted with halo, pseudohalo, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, alkoxycarbonyl, aryl, halosulfonyl, or haloalkoxy; and 6w) R4 is -C (0) N (R21) R22 and R21 and R22, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or a heteroaryl ring optionally substituted with halo, pseudohalo, alkyl, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, alkoxycarbonyl, aryl, halosulfonyl or haloalkoxy; 6x) R6 and R7 are independently hydrogen, optionally substituted alkyl, -OR14, or R6 and R7 together form an optionally substituted cycloalkyl ring, an optionally substituted heterocyclyl ring or an optionally substituted -cycloalkenyl ring; and 6y) R4, R ?, R6 and R7, when substituted, are independently substituted with halo, pseudohalo, alkyl, alkoxy, alkylenedioxy, haloalkyl, nitro, cyano, alkoxycarbonyl, aryl, halosulfonyl, or haloalkoxy. In another embodiment, Y is CR33 and R30 as defined above in the Brief Description of the Invention. In another embodiment, Y is CR30 and Z is CR31, and R30 and R31 are as defined above in the Brief Description of the Invention. In another embodiment, R30 and R31 are each independently selected from the group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, aralkyl optionally substituted, optionally substituted heteroaralkyl, -OR32, -SR32, N (R33) R34, -N (R33) S (0) 2R23; -N (R35) N (R33) R34, -N (R3S) N (R33) S (O) 2R23, -C (0) R36, -C (0) OR32, -C (S) OR32, -C ( 0) SR32, -C (0) N (R33) R34, -C (0) N (R33) S (0) 2R23 and -C (0) N (R35) N (R33) R34 or C (0) N (R3?) N (R33) S (0) 2R23. Preferred embodiments are those compounds wherein X is -N (R9); And it's CR30 and Z is CR31. A further preferred embodiment are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) 0R14, -C (S) 0R14, -.C, - (0) SR14, -C (0) N (R1S) R1S, -C (O) N (R15) S (0) 2R23, -C (O) N (R15) N = R16, -C (0) N (R17) N (R15) R16 or -C (0) N (R17) N (R15) S (0) 2R23; R2 is hydrogen, halo or alkyl; R3 is -C (0) R10; R4, R5, Rs and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl; R6 and R7 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl ring, an optionally substituted heterocyclyl ring or an optionally substituted cycloalkenyl ring, and R4 and R5 are as described above; R9 is hydrogen, optionally substituted alkyl, C (0) R18, -C (0) OR20 or -S (0) 2R23; R10 is an optionally substituted aryl or an optionally substituted heteroaryl; R14, R15, R1S, R17, R20 and R23 are as described above in the Brief Description of the Invention. R30 and R31 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring, an optionally substituted cycloalkenyl ring, an optionally substituted cycloalkynyl ring, an optionally substituted heterocyclyl ring, an optionally substituted heteroaryl ring or an aryl ring optionally replaced, I provide however that the arillo can not be phenyl. Other preferred embodiments are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) 0R14 or -C (0) N (R15) R1S; R2 is hydrogen, halo or optionally substituted alkyl; RJ is -C (0) R; R4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -C (0) N (R21) R22 or -C (0) 0R20; R5, R6 and R7 are each independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or R6 and R7 together with the carbon to which they are attached, form a heterocyclyl ring, an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring and R5 is as described above; R9 is hydrogen, optionally substituted alkyl, -C (0) R13, -C (0) OR20. - or -S (0) 2R23; R10 is independently optionally substituted aryl or optionally substituted heteroaryl; R14, R15 and R16 are each independently hydrogen, an optionally substituted alkyl ring or an optionally substituted cycloalkyl ring; R20, R21 and R22 is as described above in the Brief Description of the Invention; R30 and R31 together with the carbon atoms to which they bond, form a cycloalkyl ring. A preferred compound of this embodiment is ethyl ester of 3- (4-Fluoro-benzoyl) -1,1-dimethyl-1,2,3,7,7,8,9,10-octahydro-azepino [4, 5-b] indole-5-carboxylic acid. Other preferred embodiments are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) OR14 or -C (0) N (R15) R16; R2 is hydrogen, halo or optionally substituted alkyl; R3 is -C (0) R10; R4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, C (0) N (R21) R22 or -C (0) OR2 °; R5, R6 and R7 are each independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or R6 and R7, together with the carbon to which they are bonded, form a heterocyclyl ring, an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring and R5 is as described above; R9 is hydrogen, optionally substituted alkyl, -C (0) R18, -C (0) OR20, or -S (0) 2R23; R10 is independently optionally substituted aryl or optionally substituted heteroaryl; R14, R15 and R1S are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; R20, R21 and R22 are as described above in the Brief Description of the Invention; R30 and R31 together with the carbon atoms to which they bind, form a cycloalkyl ring substituted with halo, pseudohalo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halosulfonyl, nitro, -OR70, SR70, -R60-C (= J) R71, -R60-N (R70) C (O) R71 / -OC (0) R71, -R60-N (R75) (R76), -N (R70) S ( O) 2R71 and -S (0) 2R71; each R60 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl, -OR72 or -N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or a heteroaryl ring; and R7? and R76 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R76 together with the nitrogen atom to which they bind, form a heterocyclyl ring or a -heteroaryl ring. Other preferred embodiments are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) 0R14 or -C (O) N (R15) R15; R2 is hydrogen, halo or optionally substituted alkyl; R3 is -C (0) R10; R4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, C (O) N (R21) R22 or -C (O) OR20; R5, R6 and R7 are each independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or Re and R7, together with the carbon to which they are bonded, form a heterocyclyl ring, an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring and R5 is as described above; R9 is hydrogen, optionally substituted alkyl, -C (0) R18, -C (O) OR20 or -S (0) 2R23; R10 is independently optionally substituted aryl or optionally substituted heteroaryl; R14, R15 and R1S are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; R20, R21 and R22 is as described above in the Brief Description of the Invention; R30 and R31 together with the carbon atoms to which they bond, form a heterocyclyl ring. Other preferred embodiments are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) 0R14 or -C (0) N (R15) Rls; R2 is hydrogen, halo or optionally substituted alkyl; R3 is -C (0) R10; R4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, C (0) N (R21) R22 or -C (0) 0R2 °; R5, Rs and R7 are each independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or R6 and R7 together with the carbon to which they are attached, form a heterocyclyl ring, an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring and R5 is as described above; R9 is hydrogen, optionally substituted alkyl, -C (0) R18, -C (0) OR20 or -S (0) 2R23; R x is independently optionally substituted aryl or optionally substituted heteroaryl; R14, RX? and R16 are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; R20, R21 and R22 are as described above in the Brief Description of the Invention; R30 and R31 together with the carbon atoms to which they bind, form a heterocyclyl ring substituted with halo, pseudohalo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halosulfonyl, nitro, -OR70, SR70, -RS0-C (= J) R71, -R60-N (R70) C (O) R71, -0C (0) R71, -R50-N (R75) (R76), -C (R70) S ( O) 2R71 and -S (0) 2R71; each RS0 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl-, -OR72 or ~ N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74 together with the nitrogen atom to which they bind, form a heterocyclyl or heteroaryl ring; and R75 and R7e are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R7S, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl ring. Other preferred embodiments are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) OR14 or -C (O) N (R15) R1S; R2 is hydrogen, halo or optionally substituted alkyl; R3 is -C (0) R10; R 4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, C (0) N (R21) R22 or -C (0) OR20; R5, R6 and R7 are each independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or R6 and R7, together with the carbon to which they are bonded, form a heterocyclyl ring, an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring and Rs is as described above; R9 is hydrogen, optionally substituted alkyl, -C (0) R18, -C (0) OR20 or -S (0) 2R23; R10 is independently optionally substituted aryl or optionally substituted heteroaryl; R14, R15- and R1S are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; R20, R21 and R22 is as described above in the Brief Description of the Invention; R30 and R31 together with the carbon atoms to which they bond, form a heteroaryl ring. Other preferred embodiments are those compounds wherein X is -N (R9); And it's CR30; Z is CR31; R1 is -C (0) 0R14 or -C (0) N (R15) R16; R2 is hydrogen, halo or optionally substituted alkyl; R3 is -C (0) R10; R 4 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, C (0) N (R 21) R 22 or -C (O) 0 R 20; R5, Rs and R7 are each independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or Rd and R7, together with the carbon to which they are attached, form a heterocyclyl ring, an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring and R5 is as described above; R9 is hydrogen, optionally substituted alkyl, -C (0) R18, -C (0) 0R20 or -S (0) 2R23; R10 is independently optionally substituted aryl or optionally substituted heteroaryl; R14, R15 and R16 are each independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; R20, R21 and R22 is as described above in the Brief Description of the Invention; R30 and R31 together with the carbon atoms to which they bind, form a heteroaryl ring substituted with halo, pseudohalo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halosulfonyl, nitro, -OR70, SR70, -R60-C (= J) R71, -RS0-N (R70) C (O) R71, -OC (0) R71, -R60-N (R75) (R76), -N (R70) S ( O) 2R71 and ~ S (0) 2R71; each R60 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl, -OR72 or -N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl ring; and R75 and R76 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R7S, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl ring. Another embodiment is a compound having the formula (III): or a pharmaceutically acceptable derivative thereof, wherein: R1 is -C (0) 0R14, -C (S) 0R14, -C (0) SR14, -C (O) N (R15) R16, -C (0) N (R15) S (0) 2R23, -C (0) N (R15) N = Rld, -C (O) N (R17) N (R15) R? E or -C (0) N (R17) N (R15) S (0) 2R23; R2 is hydrogen, halo or alkyl; R3 is -C (O) R10; R4 is selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -C (0) 0R20 and -C (0) N (RX1) R12; R5, R6 and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; or Rs and R7 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl or an optionally substituted cycloalkenyl ring, and R5 is as described above, - R9 is hydrogen, optionally substituted alkyl, C ( 0) R18, -C (0) 0R20 or -S (0) 2R23; and R10 is an optionally substituted aryl or an optionally substituted heteroaryl; and R30 and R31 are each independently selected from a group consisting of optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -C (0) R36, -C (0 ) 0R32, -C (S) 0R32, -C (0) SR32, C (0) N (R33) R23, -C (0) N (R33) S (0) 2R23, -C (0) N (R35) ) N (R33) R34 and -C (0) N (R35) N (R33) S (0) 2R23; or R30 and R31 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl ring, an optionally substituted cycloalkenyl ring, an optionally substituted cycloalkynyl ring, an optionally substituted heterocyclyl ring, an optionally substituted heteroaryl ring-or a ring optionally substituted aryl, providing, however, that the aryl can not be phenyl. In another embodiment, the invention comprises a pharmaceutical composition comprising a compound of the invention, and at least one additional active agent selected from antihyperlipidemic agents, agents that elevate HDL in plasma, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors, inhibitors of HMG CoA reductase, inhibitors of coenzyme A-acyl: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemf-? brizol, vitamin B6, vitamin B12, vitamin. C, vitamin E, β-blockers, anti-diabetes agents, sulfonylureas, biguanides, thiazolidinediones; activators of PPARa, PPARβ and PPAR ?, dehydroepiandrosterone, antiglucocorticoids, TNFa inhibitors, a-glucosidase inhibitors, pramlintide, amylin, insulin, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, receptor antagonists, fibrinogen, LXR a agonists, partial agonists or antagonists, LXR ß agonists, partial agonists or antagonists, phenylpropanolamine, phentermine, diethylpropione, mazindol, fenfluramine, dexfenfluramine, fentiramine, ß3 adrenoceptor agonists, sibutramine, gastrointestinal lipase inhibitors, neuropeptide Y , enterostatin, colecitoquinine, bombesin, amylin, histamine H3 receptor agonists or antagonists, dopamine D2 receptor agonists or antagonists, melanocyte stimulating hormone, corticotropin releasing factor, leptin, galanin or gamma amino butyric acid (GABA), aspirin or fibric acid derivatives, simultaneously with, prior to, or after administration of the compound of the invention. Another embodiment of the invention is a method which comprises administering at least one additional active agent selected from antihyperlipidemic agents, agents that raise HD1 in plasma, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors, HMG CoA reductase inhibitors, coenzyme A-acyl: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizole ,. vitamin B6, vitamin B12, anti-oxidant vitamins, β-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, LXR agonists, agonists or partial antagonists, LXR ß agonists, partial agonists or antagonists, or acid derivatives -5- _iíbr.ica. /! simultaneously with, prior to, or after the administration of the compound of the invention. Another embodiment of the invention is a method which comprises administering at least one additional active agent selected from sulfonylureas, biguanides, thiazolidinediones; activators of PPARa, PPARβ, and PPAR ?; agonists, LXR ß agonists, partial agonists or antagonists, LXR ß agonists, partial agonists or antagonists, dehydroepiandrosterone; antiglucocorticoids; TNFa inhibitors; inhibitors of a-glucosidase, pramlintide, amylin, insulin or insulin, simultaneously with, prior to, or after administration of the compound of the invention. Another embodiment of the invention is a method that administers at least one additional active agent selected from phenylpropanolamine, phentermine, diethylpropionate, mazindol, fenfluramine, dexfenfluramine, fentanyl, ß3-adrenoceptor agonists, sibutramine, gastrointestinal lipase inhibitors, LXR agonists, partial agonists or antagonists, LXR ß agonists, partial agonists or antagonists, neuropeptide Y, enterostatin, cholecytosine, bombesin, amylin histamine H3 receptor agonists or antagonists, D2 dopamine receptor agonists or antagonists, melanocyte stimulating hormone, corticotrophin releasing factor, leptins, galanin or gamma amino butyric acid (GABA) simultaneously with, prior to, or after the administration of the compound of the invention. Another embodiment of the invention is a method to prevent or reduce the risk of the presence of, or complications that arise from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, atherosclerotic disease events, atherosclerotic cardiovascular disease, syndrome X , diabetes mellitus, type II diabetes, insulin insensitive diabetes, hyperglycemia, cholestasis and obesity in a subject, which comprises administering a prophylactically effective amount of a compound of the invention. Another embodiment of the invention is a method for reducing cholesterol levels in plasma, in a subject in need thereof, which comprises administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for reducing the levels of triglycerides in the plasma in a subject in need thereof, which comprises administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for treating, preventing or ameliorating one or more symptoms of a disease or disorders which affect cholesterol, abnormal triglyceride or bile acid levels, which comprises administering to a subject in need thereof an effective amount of a compound of the invention. Another embodiment of the invention is a method for modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, comprising administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal comprising administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretion, excretion or pooled composition of bile acid in a mammal comprising administering an amount of a compound of the invention. Another embodiment of the invention is a method for treating, preventing or ameliorating one or more symptoms of a disease or disorder in which the activity of the nuclear receptor involved, comprising administering to a subject in need thereof an effective amount of a compound of the invention. In another embodiment, the disease or disorder is selected from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, atherosclerotic disease events, atherosclerotic cardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitive diabetes, hyperglycemia, cholestasis and obesity. In another embodiment, the disease or disorder is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, and dyslipidemia. In another embodiment, the disease or disorder is selected from the group consisting of atherosclerosis, atherosclerotic disease, atherosclerotic disease events, and atherosclerotic cardiovascular disease. In another embodiment, the disease or disorder is selected from the group consisting of syndrome X, diabetes mellitus, type II diabetes, insulin insensitive diabetes and hyperglycemia. In another embodiment, the disease or disorder is hyperlipidemia. In another embodiment, the disease or disorder is hypertriglyceridemia. In another embodiment, the disease or disorder is hypercholesterolemia. In another embodiment, the disease or disorder is obesity. In another embodiment, the disease or disorder is cholestasis. In another embodiment of the invention, the compound of the invention is a farnesoid X receptor agonist, partial agonist, antagonist or partial antagonist. Another embodiment of the invention is a method for treating, preventing or ameliorating one or more symptoms of a disease or disorder in which farnesoid X receptor activity is involved, comprising administering to a subject in need thereof an effective amount of a compound of the invention. Another embodiment of the invention is a method which further comprises administering at least one additional active agent selected from antihyperlipidemic agents, agents that raise HDl in plasma, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors, HMG CoA reductase inhibitors, coenzyme inhibitors. A-acyl: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizole, vitamin B6, vitamin B12, vitamin C, vitamin E, β-blockers, anti-diabetes agents, sulfonylureas, biguanides, thiazolidinediones; activators of PPARa, 'PPARβ and PPAR ?, dehydroepiandrosterone, antiglucocorticoids, TNFa inhibitors, - inhibitors of α-glucosidase, pra lintide, amylin, insulin, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, antagonists of the fibrinogen receptor, LXR a agonists, partial agonists or antagonists, LXR ß agonists, partial agonists or antagonists, phenylpropanolamine, phentermine, diethylpropionate, mazindol, fenfluramine, dexfenfluramine, fentiramine, β3-adrenoceptor agonists, sibutramine, gastrointestinal lipase inhibitors , neuropeptide Y, enterostatin, colecitoquinine, bombesin, amylin, histamine H3 receptor agonists or antagonists, dopamine D2 receptor agonists or antagonists, melanocyte stimulating hormone, corticotropin releasing factor, leptin, galanin or gamma amino butyric acid ( GABA), aspirin or fibric acid derivatives, in line with, prior to, or after administration of the compound of the invention. Another embodiment of the invention is a method which further comprises administering at least one additional active agent selected from antihyperlipidemic agents, agents that raise HDl in plasma, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors, HMG CoA reductase inhibitors, A-Acyl Coenzyme: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzof ibrate, cipof ibrate, gemfibrizol, vitamin B6, vitamin Bi2, antioxidant vitamins, ß blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, LXR agonists, partial agonists or antagonists, LXR ß agonists, partial agonists or antagonists, or fibric acid derivatives, simultaneously with, prior to, or after administration of the compound of the invention. Another embodiment of the invention is a method further comprising administering at least one additional active agent selected from sulfonylureas, biguanides, thiazolidinediones; activators of PPARa, PPARβ, and PPAR ?; agonists, LXR a agonists, partial agonists or antagonists, LXR ß agonists, partial agonists or antagonists, dehydroepiandrosterone; antiglucocorticoids; TNFa inhibitors; inhibitors of a-glucosidase, pramlintide, amylin, insulin or insulin, simultaneously with, prior to, or after administration of the compound of the invention. Another embodiment of the invention is a method which further comprises administering at least one additional active agent selected from f-enylpropanolamine, phentermine, diethylpropionate, mazindol, f-enfluramine, dexph enfluramine, fentirine, β3-adrenoceptor agonist agents, sibutramine, inhibitors. of the gastrointestinal lipase, LXRa agonists, partial agonists or antagonists, LXRβ agonists, partial agonists or antagonists, neuropeptide Y, enterostatin, colecitoquinine, bombesin, amylin, histamine H3 receptor agonist or antagonist, dopamine D2 receptor agonist or antagonist, Melanocyte stimulating hormone, corticotrophin releasing factor, leptin, galanin or gamma amino butyric acid (GABA) simultaneously with, prior to, or after administration of the compound of the invention. Another embodiment of the invention is a method to prevent or reduce the risk of the presence of, or complications that arise from, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease., events of atherosclerotic disease, atherosclerotic cardiovascular disease, syndrome X, diabetes mellitus, type II diabetes, insulin insensitive diabetes, hyperglycemia, cholestasis and obesity in a subject, which comprises administering a prophylactically effective amount of a compound of the invention. Another embodiment of the invention is a method for reducing cholesterol levels in plasma, in a subject in need thereof, which comprises administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for reducing plasma triglyceride levels in a subject in need thereof, which comprises administering an effective amount of a compound of the invention. Another embodiment of the invention is a method of treating, preventing or ameliorating one or more symptoms of a disease or disorder which affect cholesterol, abnormal triglyceride or bile acid levels, which comprises administering to a subject in need thereof an effective amount. of a compound of the invention. Another embodiment of the invention is a method for modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, which comprises administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal comprising administering an effective amount of a compound of the invention. Another embodiment of the invention is a method for modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretion, excretion or pooled composition of bile acid in a mammal comprising administering an amount of a compound of the invention.

C. Preparation of the compounds of the invention The starting materials in the synthesis examples provided herein are either available from commercial sources or by means of literature procedure (eg, March Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (1992) 4th Ed., Wiley Interscience, New York). All commercially available compounds are used without further purification unless indicated otherwise. CDC13 (99.8% D, Cambridge Isotope Laboratories) is used in all experiments as indicated. Nuclear magnetic resonance (NMR) spectra of protons (^?) Were recorded on a Bruker Avance 400 MHz NMR spectrometer. The important peaks are tabulated and typically include: number of protons, and multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multipleto; br s, broad singlet). Chemical changes are reported as parts per million (d) relative to tetramethylsilane. The low resolution mass spectra (MS) are obtained as electrowinning ionisation mass spectra (ESI), which are recorded in an instrument Perkin-Elmer SCIEX CLAR / EM using reverse phase conditions (acetonitrile / water, 0.05% trifluoroacetic acid). Instant chromatography is done using silica gel Merck 60 (230-400 mesh) following the standard protocol (Still et al. (1978) J. Org. Chem. 43: 2923).

It will be understood that in the following description, combinations of substituents and / or variables of the detailed formulas are permissible only if such contributions result in stable compounds. It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediary compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups of hydroxy include trialkylsilyl or diarylalkysilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups of amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C (0) -R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups of carboxylic acid include alkyl, aryl or aralkyl esters. The protecting groups can be added or removed in accordance with standard techniques, which are known to those skilled in the art and described herein The use of protecting groups is described in detail in Green, T.

W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-interscience. In the following reaction schemes, unless noted otherwise, the various substituents R and the symbols X, Y and Z are as defined above in the Brief Description of the Invention, and A is halo. Someone skilled in the art could easily guess which selections for each substituent are possible for each reaction condition of each reaction scheme. However, the substituents are selected from the components as indicated in the above specification, and may be linked to starting materials, intermediates and / or end products according to the reaction schemes known to those of ordinary skill in the art. It will also be apparent that many of the products may exist as one or more isomers, that is isomers, enantiomers and / or diastereomers E / Z. Provisional application Serial No. 60 / 383,574, filed May 24, 2002, and its corresponding non-provisional application Serial No. 10 / 447,302, filed May 27, 2003, which describes in additional detail certain information background, procedures, compounds and / or compositions are presented as a reference in their entirety.

Reaction Scheme 1 describes the general synthesis of compounds of formula I. In general, hetero-3-yl-2-ethylamines (1) are condensed with haloketones (2) (or haloaldehydes) and undergo subsequent reconfiguration to give azepines (3), which can then react with electrophiles to provide products (4) of formula 1. In particular, heteroar-3-yl-2-ethylamines (1) (where R4-R7 are described above in the Brief Description of the invention) may consist of optionally substituted imidazole-4-ylethylamines (X = NR9, Y = CR30, Z = N), optionally substituted pyrrol-3-yl-2-ethylamines (X = NR9, Y = CR30, Z = CR31) or thiophen-3-yl-2-ethylamines (X = S, Y = CR30, Z = CR31). For example, a haloketone (2) can be chlorine or bromopyruvate (Rx = C02R and R2 = H) and the electrophiles can be acyl or sulfonyl chlorides, chloroformates, isocyanates or isothiocyanates (R3 = COR, S02R, C02R, CONRR 'and CSNRR', respectively).

REACTION SCHEME 1 R2 2 As described in Reaction Scheme 2, commercially available ethylamines (la) can be prepared from commercially available material such as compounds 5-10. There are a variety of approaches for the synthesis of compounds 5 (Katritzky, Comprehensive Heterocyclic Chemistry, Elsevier Science, 1997, Joule et al, Heterocyclic Chemistry, 3d Ed., Chapman S Hall, 1995). The aldehydes (6) can be prepared from the compounds 5 by means of formylation, for example, with dichloromethyl methyl ether and aluminum chloride (Cárter et al., J. Am. Chem. Sos. 1987, 109, 2711- 2717). The reduction of aldehydes (6) with sodium borohydride can provide alcohols (7) (Ladduwahetty et al., J. Med. Chem. 1996, 39, 2907-2914). The alcohols (7) can be transformed into halides (8) (Turner et al., J. Am. Chem. Soc. 1949, 71, 2801, Michailow et al., Zh. Obshch. Khim., 1957, 27, 726). Substitution of halides (8) with cyanide can provide acetonitriles (9) (Potvin et al., Tetrahedron Asymmetry, 1996, 10, 2821-24; Madronero et al., Eur. J. Med. Chem. Chim. Ther., 1974, 9 , 445-448). Optional alkylation of 9 can be followed by reduction, for example, with lithium aluminum hydride, to give the heteroaryl-3-yl-2-ethylamines (la).

REACTION SCHEME 2 X AAIICCI3 6 7 LIAIH4 8 9 10 R * Rt? Y-? NH2 1a A more specific example of the structure compound (la) (3- (2-aminoethyl) pyrrole-2-carboxylate) can also be synthesized by means of the dimethylaminomethylpyrrolo 7a intermediate as shown in Reaction Scheme 2a. The aldehydes (6a) can be prepared from the compounds 5 by means of formylation with dichloromethyl methyl ether and aluminum chloride. Reductive amination of aldehydes (6a) with dimethylamine / sodium borohydride can provide dimethylamines (7a) (Ladduwahetty et al., J. Med. Chem. 1996, 39, 2907-2914). The dimethylamines (7a) can be transformed into a quaternary ammonium salt (8a). Substitution of the trimethylammonium salt of (8a) with cyanide can provide acetonitriles (9a). The protection of the nitrogen atom of 9a with a Boc group can be followed with optional alkylation and deprotection to provide 10a. Reduction of nitrile 10a with Raney nickel in formic acid can provide 3- (2-aminoethyl) pyrrole-2-carboxylate (la).

REACTION SCHEME 2A 5th 6th 7th 10a 1a As described in Reaction Scheme 3, e.thylamines (Ib) can be prepared from nitroolefins (eleven) . The condensation of nitroalkanes with aldehydes (6) in the presence of a base provides the nitroolefins (11) (Hamdan et al., Synth, Commun., 1985, 15, 71-74, Arnold et al., J. Heterocycl, Chem. 1990, 27, 1169-1171), which can be reduced with lithium aluminum hydride to give the ethylamines ( Ib).

REACTION SCHEME 3 As described in Reaction Scheme 4, the formation of the azepine ring can be performed by a Pictet-Spengler reaction and a subsequent reconfiguration. Amines (1) (with HCl added in situ) or their hydrochloride salts can react with 3-halopyruvates (2a) in the corresponding alcohols under reflux to provide piperidine derivatives (12), which are then heated under basic conditions, that is, with ASD or in pyridine, to give the azepine compounds (13). Subsequent treatment of 13 with electrophiles, that is, acyl or sulfonyl chlorides, isocyanates and chloroformates, in the presence of a base, eg, TEA, provides the final products 14 (Kuehne et al. (1985) J. Org. Chem 50: 919-924).

REACTION SCHEME 4 Piri Re Similarly, other haloketones (2) (eg, Rx = alkyl or aryl) can undergo a similar reaction sequence to provide the corresponding azepines (15), as described in Reaction Scheme 5.

REACTION SCHEME 5 As described in Reaction Scheme 6, the indole benzene ring can be selectively reduced to give a saturated ring. The formation of the indolazepine ring can be carried out by a Pictet-Spengler reaction and a subsequent reconfiguration. Thus, for example, the tryptamines (le, X = NR9) can react with a haloketone such as 3-halopiruvates (2a) to provide the β-carboline intermediates (16), which are then heated under basic conditions, ie , with ASD or in pyridine, to give the azepines (17) (Kuehne et al. (1985) J. Org. Chem. 50: 919-924) where R8 is as defined in the non-provisional application, serial no. 10 / 447,302. Subsequent treatment of 17 with electrophiles, that is, acyl or sulfonyl chlorides, isocyanates and chloroformates, in the presence of a base, for example, TEA, provides the end products 18. In addition, the azepino [4,5-b] benzofurans (18, X = O) and azepino [4, 5-b] benzothiophenes (18, X = S) can be prepared in a similar manner from the respective heteroar-3-yl-2-ethylamines (le, X = O or S). The benzene ring of azepinoindole can be reduced by hydrogenation mediated by Adam catalyst under 40 psi (2.81 kg / cm 2) of hydrogen (Boekelheide &Liu, J. Am. Chem. Spe. 1952, 74, 4920-4922) to give the compound 19, which can be converted to compound 20, for example, by oxidation with tert-butyl hypochlorite to reinstall the double bond (Kuehne et al (1985) J. Org Chem. 50: 919-924) . When the hydrogenation mediated by Adam catalyst is carried out under a hydrogen atmosphere, compound 18 is selectively reduced to give compound 20.

Reaction Scheme 6 19 20 X = NR9, O or S (0) t where t is 0 to 12 The following reaction schemes describe the formation of several azepino [4, 5-b] Índoles (18, X = NR9), azepino [4, 5-b] benzofurans (18, X = O) and azepino [4,5-b] benzothiophenes (18, X = S) substituted, all of which can undergo the step of reduction mediated by the Adams catalyst followed by the step of oxidation by tert-butyl hypochlorite to reinstall the double bond to provide the corresponding compound 20. Reaction Scheme 7 generally describes the synthesis of azepino [4,5-b] indoles (22, X = NR 9), azepino [4, 5-b] benzofurans (22, X = 0) and azepiho [4, 5-b] benzothiophenes (22, X = S) from heteroar-3-yl-2-ethylamines (le, X = NR9, O or S) and haloketones (2) (for example, R1 and R2 = alkyl or aryl).

REACTION SCHEME 7 The haloketones (2) or halopiruvates (2a) in Reaction Schemes 6 6 1 are either commercially available or can be prepared rapidly by means of common literature procedure. In particular, the 3 -halopiruvates (2a, R2 = H) can be prepared by esterification of the corresponding alcohols (RxOH) with 3-halopyrubic chloride (23) (Teague, et al, Bioorg. & Med. Chem. Lett., 1995, 5, 2341-2346) as described in Reaction Scheme 8.

REACTION SCHEME 8 A = Cl or Br 23 2a As described in Reaction Scheme 9, the higher 3-halopyruvates (2b) (eg, R = alkyl) can be synthesized by oxidative bromination of a-hydroxyesters (24) (Heterocycles 1991, 32, 693). Although the non-hydrogen substituent R can be incorporated into the final azepine products (22), the following reaction schemes characterize examples that are simplified by default of R2.

REACTION SCHEME 9 * Some substituted tryptamines (28, X = NR9) are commercially available, although many can be prepared from Índoles (25, X = NR9) as described in Reaction Scheme 10. For example, the indoles (25) can be formulated to give the aldehydes (26, X = NR9) (Mor et al., J. Med. Chem. 1998, 41, 3831-3844). These 3-formylindoles (26) can undergo a Henry reaction (Rosini Comp.Org Syn. 1991, 2, 321-340) with 1-nitroalkanes to provide nitroalkenes (27, X = NR9), which can be reduced (ie , catalytic hydrogenation or lithium aluminum hydride) and then treated with HCl to provide tryptamine hydrochlorides (28). Similarly, other substituted heteroar-3-yl-2-ethylamines (28, X = O or S) can be synthesized from their corresponding heterocycle (25), that is, benzofurans and benzothiophenes. A variety of indoles can also be prepared by synthetic Fischer means of indol (S & amp;; March, March's Advanced Organic Chemistry, 5th Ed., John Wiley and Sons: NY, 2001, ppl453-24).

REACTION SCHEME 10 26 27 28 As described in Reaction Scheme 11, other substituted tryptamines (33) can also be prepared. The protection of 3 - indolyl acetonitriles (31), for example, with Boc (tert-butoxycarbonyl) followed by mono- or dialkylation, and then deprotection can provide the substituted 3-indolyl acetonitriles (32). Reduction of 32, for example, with lithium aluminum hydride, followed by treatment with HCl affords tryptamine hydrochlorides 33. Thus, for example, the monoalkyl species (32, R = H, Rs) can be prepared by the addition of 1 equivalent of alkyl halide. The Gem-dialkyl species (32, R = R6 = R7) can be prepared from 2 equivalents of alkyl halide and the hetero-dialkyl species (32, R = R6, R7) can be prepared during the sequential addition of 1 equivalent of each of two alkyl halides. Intermediates (31) can be easily prepared from gramin (30), which are either commercially available or are synthesized from. índoles (29) (Brown and Carrison, J. Chem. Chem. Soc. 1955.77, 3839-3842). In general, gramin (30) can be treated with methyl iodide to form a quaternary ammonium salt, which can be displaced with cyanide to give 3-indolyl acetonitriles (31). Benzofuran-3-yl and benzo [b] thiophen-3-yl ethylamines (28, X = O, or S) can be prepared using similar methods, in which the protection and deprotection steps are not required.

REACTION SCHEME 11 RB C 29 30 31 3) TFA 32. 33 The preparation of spirocyclic analogues (35) of tryptamine can also be performed as described in Reaction Scheme 12. For example, intermediate 31 can be protected with benzyl bromide followed by alkylation with an alkyl dihalide, for example, 1.4 -dibromobutane, to provide the corresponding intermediate (34, n = 2). Subsequently, the 34 can be reduced, deprotected (for example, with sodium metal in liquid ammonia) and treated with HCl to provide the spiro-substituted tryptamine hydrochloride.

REACTION SCHEME 12 As described in Reaction Scheme 13, substituted tryptamines (38, X = NR9) can also be prepared by knoevenagel condensation of 3-indolyl acetonitrile (36, X = NR9) with an aldehyde to provide acrylonitriles (37, X = NR9 ). Subsequent reduction, for example, Raney nickel, and treatment with HCl can provide tryptamine hydrochlorides (38). Benzofuran-3-yl and benzo [b] thiophen-3-yl ethylamines (38, X = 0, or S) can also be prepared using analogous methods.

Reaction Scheme 14 describes the synthesis of hexahydroazepine compounds (40) by means of the reduction of azepines (39). For example, tetrahydroazepino [4,5-b] indoles 39 (X = NR 9) can be reduced with NaBH 3 CN to give hexahydroazepino [4,5-b] indoles (Kuehne et al (1985) J. Org. Chem. : 919-924), which can be treated with an electrophile, for example, acyl chloride, to provide the corresponding azepine product (41).

REACTION SCHEME 14 39 40 41 Reaction Scheme 15 describes the conversion of 5-esters 40 to 5-amides (44) by means of a multi-step reaction sequence starting with the hexahydroazepine compounds (40). For example, tetrahydroazepino [4, 5-b] Índles (17, A = NR9) can be reduced with NaBH3CN to give hexahydroazepino [4,5-b] indoles (Kuehne et al. (1985) J. Org. Chem. 50: 919-924), which can be treated with several amines to give the corresponding amides (42), which can then be reacted with an electrophile, for example, an acyl chloride, to provide the corresponding amide (43). Oxidation of 43 with tert-butyl hypochlorite (Kuehne et al (1985) J. Org. Chem. 50: 919-924) can then provide the azepine product (44).

REACTION SCHEME 15 43 44 A more general approach to the modification of the 5-ester group is described in Reaction Scheme 16. Azepine (41) can be saponified to give the respective acid (Four. Five) . A nucleophile RBH (ie, alcohols, phenols, -amines, thiols) can be coupled with, for example, using carbonyldiimidazole (CDl), followed by oxidation with tert-butyl hypochlorite to provide azepine (47).

REACTION SCHEME 16 The heterocyclyl groups can be introduced into the 5-position of the acid (45). For example, as described in the Reaction Scheme, 17 oxazolines are prepared by forming amides (49) from the respective 'amino alcohols and acids (45). The resulting amides (49) can then be cyclized, for example, by treatment with thionyl chloride followed by a strong base, to provide the corresponding heterocycle (51). The halogenation and subsequent dehydrohalogenation of the intermediate (50) (not isolated) can occur under the reaction conditions. Similar reactions can be seen for other heterocycles, that is, imidazolines and thiazolines. Also the additional oxidation would provide the corresponding heteroaromatic product, for example, oxazole.

REACTION SCHEME 17 The 5-ester group of 17 can be hydrolyzed to give 5-carboxylic acid (53). However, direct hydrolysis provides 53 in low yield. Accordingly, as described in Reaction Scheme 18, azepine (17) is transformed into the compound protected by 3-Boc (52, which can be hydrolysed under standard basic conditions with Boc elimination to provide the acid (53) .

REACTION SCHEME 18 17 52 53 As described in Reaction Scheme 19, azepine (17) can be treated with Lawesson's reagent (Curphey, et al, J. Org. Chem. 2002, 67, 6461-6473) to provide the O-alkyl thioester (54). ) which can, for example, be acylated to provide the azepine product (55).

REACTION SCHEME 19 17 54 55 Reaction Scheme 20 describes the incorporation of 3-alkyl / aryl groups. For example, azepine (17) can be treated with a base, for example, NaH, and then an alkyl halide (R3A) to provide 3-alkyl azepine (18). An aryl or heteroaryl group (R3) can be introduced by coupling 41 with boronic acids (Lam, et al, Tetrahedron Lett, 2001, 42, 3415-3418), followed by oxidation of the intermediate (41) to give the corresponding product of azepine (56).

REACTION SCHEME 20 The derivation of 2-substituted azepines (57) is described in Reaction Scheme 21. The diester (57) can be partially hydrolyzed to give the acid (58), which can be transformed into amides (59), for example, using CDI . The intermediates (59) can also be substituted during the addition of an electrophile, for example, acyl chloride, to give the corresponding diamides (60).

REACTION SCHEME 21 59 60 As described in Reaction Scheme 22, alcohol (61) can be derived by the addition of an electrophile (that is, chloride, chloroformate or acyl isocyanate). For example, 61 can be esterified in the presence of. a base for providing the diester (62), whereby a diester-amide-containing mixture (63) can result.

REACTION SCHEME 22 61 62 63 As described in Reaction Scheme 23, the 1-oxoazepines (65) can be used as key intermediates for the introduction of other functional groups. For example, azepine (64) can be oxidized, for example, with DDQ, to provide 1-oxoazepine 65, which can be redused to give the corresponding alcohol (66). Treatment of 66 with trifluoromethanesulfonic anhydride followed by the addition of nucleophiles RYH (alcohols, thiols, amines, hydroxylamines and hydrazines) can provide the corresponding azepine products (67).

REACTION SCHEME 23 66 67 Similarly, as described in the Reaction Scheme 24, 1-oxoazepine 65 can be treated with ethylene glycol under acid catalysis to form the cyclic acetal (68). Also 65 can be treated with amines, hydroxylamines and hydrazines to give imines (69, YR = NR15), oximes (69, YR = OR14) and hydrazones (69, YR = NNR15Rld), respectively. Additionally, 65 may experience a Wittig or Horner-Wadsworth-Emmons reaction (Maercker (1965) Org. React. 14: 270-490; Wadsworth, Jr. (1977) Org. React. 25: 73-253) to provide exocyclic alkylidenes (69, for example, YR = CRR ').

REACTION SCHEME 24 As described in Reaction Scheme 25, substituents on the indole ring can be introduced, that is, by means of Suzuki cross-coupling reactions and aryl amination from the corresponding aryl bromides (71). The indoles substituted with bromine 71 can be prepared by means of direct bromination of indoles (70) with NBS or from commercially available tryptamine. These intermediates (71) can be used in Suzuki cross-coupling reactions (Miyaura, et al, Chem. Rev. 1995, 956, 2457-2483) with boronic acids to provide, for example, products substituted with aryl (72, R8 = aryl) and in aryl amination reactions (Wolfe, et al, J. Org. Chem. 2000, 65, 1144-1157) to provide the amino-substituted products (72, R8 = NR28R29).

REACTION SCHEME 25 70 71 Suzuki Coupling or Aryl Amination 72 As described in Reaction Scheme 26, other transformations of functional groups may be performed, for example, in the indole ring of azepine (73). Protecting groups, such as alkyl and aryl groups, on azepine oxygen, sulfur, or nitrogen-containing substituents 73 can be removed under appropriate conditions to provide azepine (74). The treatment of 74 with electrophiles, such as carbamoyl chlorides, can provide the corresponding azepines (75), for which the substituent R8 is C (0) NR R25 in this representative example.

REACTION SCHEME 26 Electrophil Pg = protective group As described in Reaction Scheme 27, substituents at the 6N position of azepine (76) can be introduced, for example, by alkylation with a base and alkyl halide, to give the corresponding azepine (77).

REACTION SCHEME 27 76 77 D. Formulation of pharmaceutical compositions The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more modulators of nuclear receptor activity provided herein that are useful in the prevention, treatment, or alleviation of one or more of the symptoms of diseases or disorders associated with the activity of the nuclear receptor, including the activity of the farnesoid X receptor and / or the orphan nuclear receptor. Such diseases or disorders include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hyperglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerotic disease events, gallstone disease, acne vulgaris, acneiform skin conditions, type II diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by disturbed epidermal impediment function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of disorganized differentiation or excessive proliferation of the epidermis or mucous membrane, and cardiovascular disorders. In addition, the pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the nuclear receptor activity modulators provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms or disorders that are not directly associated with a nuclear receptor, but for which a complication of the disease or disorder is treatable with the claimed compounds and compositions. By way of example, without limitation, cystic fibrosis is not commonly associated with nuclear receptor activity, but can result in cholestasis, which can be treated with compounds and compositions of the subject. The compositions contain one or more compounds provided herein. The compounds are preferably formulated in appropriate pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, formulations or sustained-release elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, in addition to preparation of Transdermal patch and dry powder inhalers. Commonly the compounds described above are formulated in pharmaceutical compositions using techniques and procedures. well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126). In the compositions, effective concentrations of one or more pharmaceutically acceptable compounds or derivatives are mixed with a pharmaceutically acceptable carrier or vehicle. The compounds may be derivatives such as the corresponding salts, esters, enol ethers or esters, acids, bases, solvates, hydrates or prodrugs before formulation, as described above. The concentrations of the compounds in the compositions are effective for the delivery of an amount, in the administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders associated with nuclear receptor activity or in which the activity of nuclear receptor is involved. Such diseases or disorders include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerotic disease events, gallstone disease, acne vulgaris, acneiform skin conditions, type II diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a disturbed epidermal impediment function, hyperlipidemia, cholesteasis, peripheral occlusive disease, ischemic stroke, conditions of disorganized differentiation or excess proliferation of the epidermis or mucous membrane, and cardiovascular disorders. Commonly, the compositions are formulated for single dose administration. To formulate a composition, the weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is alleviated or improved. Carrier or pharmaceutical carriers suitable for administration of the compounds provided herein, include any of the carriers known to those skilled in the art to be appropriate for the particular mode of administration. In addition, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. Liposomal suspensions, which include tissue-directed liposomes, such as tumor-directed liposomes, may also be suitable pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV) can be formed by drying the egg phosphatidyl choline and brain phosphatidyl serine (molar ratio 7: 3) inside a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove the unencapsulated compound, they are pelleted by centrifugation, and then resuspended in PBS. The active compound is included in the pharmaceutically acceptable carrier to exert a therapeutically useful effect in the absence of undesirable side effects in the treated patient. The therapeutically effective concentration can be determined empirically by evaluation of the compounds using in vitro and in vivo systems described herein and in International Patent Application Publication Nos. 99/27365 and 00/25134 and then extrapolated therefrom for dosages to humans.

• The concentration of the active compound in the pharmaceutical composition will depend on the degrees of absorption, inactivation and excretion of the active compounds, the physicochemical characteristics of the compound, the dosage schedule and the amount administered in addition to other factors known to those of experience in the technique. For example, the amount that is supplied is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with the activity of the nuclear receptor or in which the activity of the nuclear receptor is involved, as described herein. Commonly a therapeutically effective dose should produce a serum concentration of active ingredient from about 0.1 ng / ml to about 50-100 μg / ml. The pharmaceutical compositions commonly should provide a dose of from about 0.001 mg to about 2000 mg of the compound per kilogram of body weight per day. The dosage unit dosage forms are prepared to provide from about 1 mg to about 1000 mg and preferably from about 10 to about 500 mg of the essential active ingredient or a combination of the essential ingredients per dosage unit form. The active ingredient can be administered once, or it can be divided into a number of smaller doses to be administered in time intervals. It is understood that the precise dose and duration of treatment is a function of the disease being treated and can be determined empirically using known evaluation protocols or by extrapolation of in vivo or in vitro test data. It will be noted that concentrations and dose values may also vary with the severity of the condition to be alleviated. It will further be understood that for any particular subject, the specific dose regimens should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the composition, and that the established concentration intervals here they are only exemplary and are not intended to limit the scope or practice of the claimed compositions. Pharmaceutically acceptable derivatives include forms of acids, bases, ethers and esters of enol, salts, esters, hydrates, solvates and prodrugs. The derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound. • Thus, the concentrations or effective amounts of one or more of the compounds described herein or pharmaceutically acceptable derivatives thereof are mixed with a pharmaceutically acceptable carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. The compounds are included in one. effective amount to improve one or more symptoms of, or for treatment or prevention of, diseases or disorders associated with nuclear receptor activity or in which the activity of the nuclear receptor is involved, as described herein. The concentration of the active compound in the composition will depend on the absorption, inactivation, degree of excretion of the active compound, dose schedule, amount administered, particular formulation in addition to other factors known to those skilled in the art. The compositions are intended to be administered by an appropriate route, including orally, parenterally, rectally, topically and locally. For oral administration, capsules and tablets are currently preferred. The compositions are in liquid, semi-liquid or solid form and are formulated in an appropriate manner for each route of administration. The preferred modes. of administration include parenteral and oral modes of administration. Oral administration is currently the most preferred. Solutions or suspensions used for parenteral, subcutaneous, or topical intradermal application can include any of the following components: a sterile diluent, such as water for injection, saline, fixed oil, polyethylene glycol, glycerin, propylene glycol or other solvent synthetic; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffer solutions, such as acetates, citrates and phosphates; and agents for tonicity adjustment such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material. In cases in which the compounds exhibit insufficient solubility, methods for solubilization of compounds can be used. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethyl sulfoxide (MSO), using surfactants, such as TWEEN®, or aqueous sodium bicarbonate solution. - Derivatives of the compounds, such as prodrugs of the compounds can also be used in effective pharmaceutical formulating compositions. In the mixing or addition of the compound or compounds, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends on a number of factors, including the projected mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for the improvement of the symptoms of the disease, disorder or condition treated and can be determined empirically. Pharmaceutical compositions are provided for administration to humans and animals in dosage unit forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing appropriate amounts of the pharmaceutically acceptable compounds or derivatives thereof. Therapeutically and pharmaceutically active compounds and derivatives thereof are commonly formulated and administered in unit dosage forms or multiple dose forms. The dosage unit forms as used herein, refer to discrete physically appropriate units for human and animal subjects and individually packaged as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the pharmaceutically required carrier, vehicle or diluent. Examples of unit dosage forms include ampules and syringes and individually packed tablets or capsules. Dosage unit forms can be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dose forms packaged in a single container to be administered in the form of a segregated unit dose. Examples of multiple dose forms include bottles, bottles of tablets or capsules or bottles of pints or gallons. Hence, the multiple dose form is a multiple of unit doses which are not segregated in packing. The composition may contain together with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as acacia gelatin gum, molasses, polyvinylpyrrolidone, celluloses and derivatives thereof, povidone, crospovidones and other binders known to those skilled in the art. The pharmaceutically administrable compositions can, for example, be prepared by dissolution, dispersion, or otherwise by mixing an active compound as defined above and pharmaceutically optional adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, eg, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other agents. The current methods of preparation of dosage forms are known, or will be apparent, to those skilled in the art.; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The formulation composition to be administered, in any case, will contain an amount of the active compound in an amount sufficient to alleviate the subject's symptoms. treaty. Dosage forms or compositions containing active ingredient can be prepared in the range of 0.005% up to 100% with the balance made on the non-toxic carrier. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the excipients normally employed, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium , glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems and biodegradable and biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for the preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001% -100% active ingredient, preferably 0.1-85%, commonly 75-95%. The pharmaceutically acceptable active compounds or derivatives can be prepared with carriers that protect the compound against rapid elimination from the body, such as formulations or release coatings over time. The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable derivatives thereof as described herein, may also be profitably administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in the treatment of one or more of the diseases or medical conditions referred to herein above, such as diseases or disorders associated with nuclear receptor activity or in which the activity of the nuclear receptor is involved. It is understood that such combination therapy constitutes one more aspect of the compositions and methods of treatment provided herein. 1. Compositions for Oral Administration The oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules and powders by volume. Types of oral tablets include tablets, chewable tablets and tablets which can be enteric coated, coated with sugar or film coated. The capsules may be hard or soft gelatin capsules, while the granules and powders may be provided in effervescent or non-effervescent form with the combination of other ingredients known to those skilled in the art. In certain embodiments, the formulations are solid dosage forms, preferably capsules or tablets. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder, a diluent, a disintegrating agent; a lubricant; a flow improver agent; a sweetening agent; and a flavor agent. Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Flow improver agents include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include sodium croscarmellose, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended in aluminum hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of dry dew flavors. The agents . flavors include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasurable sensation, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated lacquer and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. If oral administration is desired, the compound can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient. When the dosage unit form is a capsule, it may contain, in addition to the material of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit forms may contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as components of an elixir, suspension, syrup, water, wafer, chewing gum or the like. A syrup contains, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, inks and dyes and flavorings. The active materials can also be mixed with other active materials which do not damage the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a pharmaceutically acceptable compound or derivative thereof as described herein. Higher concentrations may be included, up to about 9-8% by weight of the active ingredient. The pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. The enteric coated tablets, due to enteric coating, resist the action of stomach acid and dissolve or disintegrate in the intestines neutral or alkaline. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. The film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle using the pharmaceutically acceptable substances mentioned above. The coloring agents can also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed, sugar coated tablets, multiple tablets and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. Oral liquid dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or reconstituted suspensions of non-effervescent granules and effervescent effervescent preparations of effervescent granules. Aqueous solutions include, for example, elixirs and syrups. The emulsions are either oil in water or water in oil. Elixirs are clear, sweetened, hydroalcoholic preparations. The pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which a liquid is dispersed in the form of small globules everywhere in another liquid.

The pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. The suspensions use pharmaceutically acceptable suspension agents and preservatives. The pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted in a liquid oral dosage form, include diluents, sweeteners and humectants. The pharmaceutically acceptable substances used in effervescent granules, to be reconstituted in a liquid oral dosage form, include organic acids and a source of carbon dioxide. The coloring and flavoring agents are used in all the above dosage forms. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic aggregate, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum and acacia. The diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and. Synthetic mixtures of compounds which produce a pleasant sensation of taste. For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, for example, in a polyethylene glycol, is. it can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example, water, to be easily measured for administration. Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt. in vegetable oils, glycols, triglycerides, propylene glycol esters (for example, propylene carbonate) and other carriers, and encapsulation of these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those set forth in U.S. Patent Nos. Re 28,819 and 4,358,603. Briefly, the formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglime, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refers to the approximate average molecular weight of polyethylene glycol, and one or more antioxidants, such as hydroxytoluene butylated (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and their esters and dithiocarbamates. Other formulations include, but are not limited to, aqueous alcoholic solutions that include a pharmaceutically acceptable acetal. The alcohols used in these formulations are any pharmaceutically acceptable water miscible solvent having one or more hydroxyl groups, including, but not imitated, propylene glycol and ethanol. Acetals include, but are not limited to, di (lower alkyl) acetals, of minor alkyl aldehydes such as acetaldehyde diethyl acetal. In all embodiments, the tablet and capsule formulations may be coated as is known to those skilled in the art for the purpose of modifying or sustaining the dissolution of the active ingredient. Thus, for example, these can be coated with an enterically conventional digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. 2. Injectables, Solutions and Emulsions. Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated here. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, improvers. of solubility, and other agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. The implementation of a slow-release or sustained release system is also contemplated here, such that a constant dosage level is maintained (see for example, US Patent No. 3,710,795). Briefly, a compound provided herein is dispersed in a solid internal matrix, for example, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, nylon : plasticized, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicon gum, polydimethylsiloxanes, silicon carbonate copolymers, hydrophilic polymers such as acrylic and methacrylic acid ester hydrogels, collagen, cross-linked polyvinyl alcohol and partially cross-linked hydrolyzed polyvinyl acetate, which is surrounded by an outer polymeric membrane, for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl-acrylate copolymers, ethylene / vinyl acetate copolymers, silicon, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, epichlorohydrin rubbers and butyl rubber, ethylene / alcohol copolymer vinyl, ethylene terpolymer o / vinyl acetate / vinyl alcohol, and ethylene / vinyl oxyethanol copolymer, which e.s soluble in body fluids. The compound diffuses through the outer polymeric membrane in a step that controls the rate of release. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, in addition to the activity of the compound and the needs of the subject. Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just before use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready for injection. be combined with a vehicle just before use and sterile emulsions. The solutions can be either aqueous or non-aqueous. If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. these. Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffer solutions, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents., isolation or chelating agents and other pharmaceutically acceptable substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations should be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, p-hydrobenzoic acid methyl and propyl esters, thimerosal, benzalkonium and benzothonium chloride. Isotonic agents include sodium chloride and dextrose. Buffer solutions include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsification agents include Polysorbate 80 (TWEEN® 80). A metal ion isolation or chelation agent includes EDTA: Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for vehicles miscible in water and sodium hydroxide, hydrochloric acid, citric acid and lactic acid to adjust pH.

The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art. Parenteral unit dose preparations are packaged in a vial, vial, or syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. The injectables are designed for local and systemic administration. A therapeutically effective dosage is commonly formulated to contain a concentration of at least about 0.1% w / w to about 90% w / w or more, preferably more than 1% w / w of the active compound to the treated tissues. The active ingredient can be administered once, or it can be divided into a number of smaller doses to be administered in time intervals. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and can be determined empirically using known evaluation protocols or by extrapolation of in vivo or in vitro test data. It will be understood that the concentrations and dosage values may also vary with the age of the individual treated. It is further understood that for any particular subject, the specific dosage regimens are adjusted over time according to the individual need and professional adjustment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein they are only exemplary and are not intended to limit the scope or practice of the claimed formulations. The compound can be suspended in micronized form or other appropriate form or it can be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on a number of factors, including the proposed mode of administration and the solubility of the compound in the carrier or vehicle selected. The effective concentration is sufficient for the improvement of the symptoms of the condition and can be determined empirically. 3. Lyophilized powders =, lyophilized powders are also of interest here, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels. The sterile lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in an appropriate solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the reconstituted powder or solution, prepared from the powder. The excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other appropriate agent. The solvent may also contain a buffer solution, such as citrate, sodium or potassium phosphate or other buffer solution such as is known to those of ordinary skill in the art, at about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art, provides the desired formulation. Generally, the resulting solution will be distributed in bottles for lyophilization. Each bottle will contain a single dosage (10-1000 mg, preferably 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as around 4 ° C at room temperature. The reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, preferably 5-35 mg, more preferably about 9-30 mg of lyophilized powder, is added per mL of sterile water or other appropriate carrier. The precise amount depends on the selected compound. The quantity can be determined empirically. 4. Topical Administration Topical mixtures are prepared as described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, dyes, pastes, foams, sprays, irrigations, sprays, suppositories, bandages, Dermal patches or any other formulation for topical administration. The pharmaceutically acceptable compounds or derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, for example, US Patent Nos. 4,044,126, 4,414,209 and 4,364,923, which discloses aerosols for delivery of a spheroid useful for the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract may be in the form of an aerosol or solution for a nebulizer, or as a microporous powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will commonly have diameters of less than 50 microns, preferably less than 10 microns.

The compounds can be formulated for local or topical application, such as for topical application to the skin and mucous membranes, as well as in the eyes, in the form of gels, creams and lotions and for application to the eyes or for intracisternal or intraspinal application . Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound can also be administered alone or in combination with other pharmaceutically acceptable excipients. These solutions, particularly those projected for ophthalmic use, can be formulated as isotonic solutions of 0.01% -10%, pH around 5-7, with appropriate salts.

. Compositions for Other Routes of Administration 10 Other routes of administration, such as topical application, transdermal patches and rectal administration are also contemplated here. Transdermal patches, which include iotrophoretic and electrophoretic devices, are well-known for those with experience in the technique. For example, patches are described in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957. The pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories used herein mean solid bodies for insertion into the rectum which melts or softens at body temperature releasing one or more pharmacological active ingredients and Therapeutically acceptable substances used in rectal suppositories are bases or vehicles and agents for the melting point Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbon dioxide (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids The combinations of the different bases can be used.Rectal suppositories can be prepared either by the compressed method or by molding.The common weight of a rectal suppository is about 2 to 3 gm Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as formulations for oral administration. 6. Directed Formulations The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be directed to a tissue, recipient, or other particular area of the subject's body to be treated. Many of the steering methods are well known to those of skill in the art. All the steering methods are contemplated here for use in the instant compositions. For examples without limitation of management methods, see, for example, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. In one embodiment, liposomal suspensions, including tissue-directed liposomes such as tumor-directed liposomes, may also be appropriate as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in the US Pat.

US No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV) can be formed by drying of egg phosphatidyl choline and brain phosphatidyl serine (molar ratio 7: 3) inside a bottle. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask is shaken until the lipid film disappears. The resulting vesicles are washed to remove the unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. 7. Handling Articles The pharmaceutically acceptable compounds or derivatives may be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for the modulation of the activity of the nuclear receptors, which include the farnesoid X receptor and / or orphan nuclear receptors or for treatment, prevention or amelioration of one or more symptoms of the nuclear receptor, which includes the farnesoid X receptor and / or orphan nuclear receptors, diseases or disorders mediated, or diseases or disorders in which the activity of the nuclear receptor, which includes the activity of the farnesoid receptor X and / or orphan nuclear receptors, is involved, within the packaging material, and a label indicating that the compound or composition or pharmaceutically acceptable derivative thereof, is used for modulation of nuclear receptor activity, which include the X-farnesoid receptor and / or orphan nuclear receptors, or for the treatment, prevention or amelioration of one or more symptoms of the nuclear receptor, which includes the farnesoid X receptor and / or orphan nuclear receptors, median diseases or disorders, or diseases or disorders in which the activity of the nuclear receptor, which includes the activity of the farnesoid X receptor and / or orphan nuclear receptors, is involved. The articles of manufacture provided herein contain packaging materials. Packaging materials for use in pharmaceutical packaging products are well known to those of skill in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, packages of ampoules, bottles, tubes, inhalers, pumps, bags, flasks, containers, syringes, bottles, and any suitable packaging material for a selected formulation and the intended method. of administration and treatment. A broad array of formulations of the compounds and -compositions provided herein are contemplated as a variety of treatments for any disease or disorder in which the activity of the nuclear receptor, including the farnesoid X receptor and / or receptor activity, is involved. orphan nuclear as a mediator or contributor to the symptoms or cause.

E. The evaluation of the activity of the compounds. Standard physiological, pharmacological and biochemical procedures are available to test compounds to identify those that possess biological activities. that modulate the activity or the nuclear receptors, which include the farnesoid X receptor and / or orphan nuclear receptors. Such assays include for example, biochemical assays such as binding assays, fluorescence polarization assays, FRET-based coactivator booster assays (see generally Glickman et al., J. Biomolecular Screening, 1 No. 1 3-10 ( 2002)), as well as based assays that include the co-transfection assay, the use of LBD-gal 4 chimeras, and protein-protein interaction assays (see, Lehmann et al., J. Biol Chem., 272 ( 6) 3137-3140 (1997). High performance exclusion separation systems are commercially available (see, for example, Zymark Corp., Hopkinton, MA.; Air Technical Industries, Mentor, OH; Beckman Instruments Inc., Fu-llerton, C ?; Precision Systems, Inc., Natick, MA) that allow these assays to run in a high performance mode. These systems typically automate complete procedures that include all reagent samples and pipettes, timed incubations dispensed with liquid and final readings from the microplate at the appropriate detector (s) for testing. These configurable systems provide high performance and fast startup as well as a high degree of flexibility and customization. The manufacturers of such systems provide detailed protocols of several high performance systems. Thus, for example, Zymark Corp. provides technical bulletins describing exclusionary separation systems for detecting the modulation of gene transcription, which bind ligands and the like.

Assays that do not require washing or liquid separation steps are preferred for such high performance exclusion separation systems and include biochemical assays such as fluorescence polarization assays (See, for example, Owicki, J., Biomol Screen 2000 Oct, 5 (5): 297) scintillation proximity assays (SPA) (see for example, Carpenter et al., Methods Mol Biol 2002; 190: 31-49) and fluorescence resonance energy transfer (FRET) or assays. reinforcement FRET-based coactivators resolved over time (Mukherjee et al., J Steroid Biochem Mol Biol 2002 Jui; 81 (3).-217-25; (Zhou et al., Mol Endocrinol. 1998 Oct; 12 (10): 1594-604) Generally such assays can be performed using either the full-length receptor or ligand binding domain isolated (LBD) In the case of the farnesoid X receptor, the LBD comprises amino acids 244 to 472 of the sequence of full length.If a ligand fluorescently labeled e is available, polarization assays provide a way to detect the binding of the nuclear receptor compounds of interest by measuring changes in fluorescence polarization that occur as a result of the displacement of a trace amount of the compound's tag ligand. Additionally this methodology can also be used to monitor the ligand-dependent association of a fluorescently labeled coactivator peptide for the nuclear receptor of interest to detect binding of the ligand to the nuclear receptor of interest. The ability of a compound to bind to a receptor,. or heterodimer complex with RXR, can also be measured in a homogeneous assay format by evaluating the degree to which the compound can compete outside of a radiolabelled ligand with known affinity for the receptor using a scintillation proximity assay (SPA). In this methodology, the radioactivity emitted by a radiolabelled compound generates an optical signal when it is brought in close proximity to a scintillation such as a bead containing Ysi copper, to which the "nuclear receptor" is linked. Nucleic receptor, the amount of light emitted from the nuclear receptor bond decreases in scintillation, can be easily detected using liquid scintillation plate readers of standard microplates such as, for example, a Wallac MicroBeta reader.The heterodimerization of the farnesoid X receptor with RXRa can be measured by fluorescence resonance energy transfer (FRET), or FRET resolved over time to monitor the ability of the compounds provided herein to bind to the farnesoid X receptor - or other nuclear receptors.Two methodologies are supported by the fact that the energy is transferred from a donor molecule to An acceptor molecule only occurs when a donor and acceptor are in close proximity. Typically, the purified LBD of the nuclear receptor of interest is then labeled with biotin and mixed with the stoichiometric amounts of europium-labeled streptavidin (Wallac Inc.), and the purified RXRa LBD is labeled with a suitable fluorophore such as CY5 ™. Equimolar amounts of each modified LDL are mixed at the same time and allowed to equilibrate for at least 1 hour prior to the addition of either variable or constant concentrations of the sample for which the affinity is determined. "After equilibration, the fluorescent signal resolved with respect to time is quantified using a fluorescent plate reader.The affinity of the compound can then be estimated from a fluorescence plate against the concentration of the added compound.This methodology can also be exploited to measure the interaction-dependent on the ligand of a co-activating peptide with a nuclear receptor to characterize the agonist or antagonist activity of the compounds described herein., the assay in this case involves the use of a domain fusion protein (LBD) that binds to a nuclear receptor ligand (GST) of the recombinant glutathione S transferase and a sequential synthetic biotinylated peptide derived from the domain that interacts with the receptor of a co-activating peptide such as the co-activator of the spheroid 1 receptor (SRC-1). Typically, GST-LBD is labeled with a europium chelate (donor) via an anti-GST antibody labeled with europium and the coactivator peptide is labeled with allophycocyanin via a streptavidin-biotin linkage. In the presence of an agonist for the nuclear receptor, the peptide is isolated from the europium that produces GST-LBD and -10 allophicocyanin in close proximity to allow energy transfer from the europium chelate to allophycocyanin. After excitation of the complex with light at 340 nm excitation energy absorbed by the europium chelate is transmitted to the portion of the allophicocyanin that fifteen - . 15 -produces an emission at 665 nm. If the europium chelate does not occur in close proximity to the allophicocyanin moiety there is little or no energy transfer and excitation of the europium chelate producing an emission at 615 nm. Thus, the intensity of light emitted at 665 nm gives a indication of the protein-protein interaction force. The activity of a nuclear receptor antagonist can be measured by determining the ability of a compound to competitively inhibit (i.e., IC50) the activity of an agonist for the nuclear receptor. In addition, a variety of cell-based assay methodologies can be used successfully in exclusion separation assays to identify and profile the specificity of the compounds of the present invention. These methodologies include the co-transfection assay, translocation assays, complementation assay and the use of gene activation technologies to overexpress endogenous nuclear receptors. There are three basic variants of the co-transfection assay strategy, co-transfection assays using the full-length nuclear receptor, co-transfection assays using chimeric nuclear receptors comprising the binding domain of the ligand of the nuclear receptor of interest. fused to a domain that binds heterologous DNA and assays based around the use of two-hybrid mammalian assay systems. The basic co-transfection assay is based on the co-transfection in the cell of an expression plasmid to express the nuclear receptor of interest in the cell with a reporter plasmid comprising a reporter gene whose expression is under the control of the sequence of DNA that is able to interact with the nuclear receptor. (See, for example, U.S. Patent Nos. 5,071,773, 5,298, 429.6, 416,957, WO 00/76523). The treatment of cells transfected with an agonist for the nuclear receptor increases the transcriptional activity of that receptor that is reflected by an increase in reporter gene expression, which can be measured by a variety of standard procedures. For receptors that function as heterodimers with RXR, such as the farnesoid X receptor, the co-transfection assay typically includes the use of expression plasmids for both nuclear receptors of interest and RXR. Typical co-transfection assays require access of the full-length nuclear receptor and appropriate response elements that provide sufficient sensitivity to exclusion by exclusion and specificity to the nuclear receptor of interest. Genes encoding the following previously described full-length proteins that are suitable for use in the co-transfection studies and the profile of the compounds described herein include the rat farnesoid X receptor (accession no. genes NM_021745), human farnesoid X receptor (accession number of gene bank NM_005123), human RXR a (accession number of gene bank NM: _002957), human RXR ß (Accession number of gene bank No. XM_042579), RXR.? Human (Accession number of gene bank No. XM_053680), LXR to human (accession number of gene bank No. NM_005693), human LXR ß (accession number of gene bank No. NM 007121), Human PPARa (accession number of gene bank No. NM_005036) and PPAR d (accession number of gene bank No. NM_006238). Reporter plasmids can be constructed using standard molecular biological techniques by placing a coding cDNA for the reporter gene in the downstream direction of an appropriate minimum promoter. For example, plasmids Luciferase reporters can be constructed by placing the cDNA encoding the firefly luciferase immediately in the downstream direction of the herpes virus from the thymidine kinase promoter (located at the nucleotide residues -105 to +51 of the nucleotide sequence of thymidine kinase) which in turn binds to the various response elements. Numerous methods that co-transfect reporter and expression plasmids are known to those skilled in the art and can be used for co-transfection assays to introduce the plasmids into a suitable cell type. Typically, such a cell does not endogenously express nuclear receptors that interact with the response elements used in the reporter plasmid. Numerous reporter gene systems are known in the art and include, for example, alkaline phosphatase Berger, J., et al. (1988) Gene 66 1-10; Kain, S. R. (1997) Methods. Mol. Biol. 63, 49-60), β-galactosidase (See, U.S. Patent No. 5,070, 012, issued December 3, 1991 by Nolan et al., And Bronstein, I., et al., (1989). J. Chemilum, Biolum 4, 99-111), chloramphenicol acetyltransferase (see, Gorman et al., Mol Cell Biol. (1982) 2 1044-51), β-glucuronidase, peroxidase, β-lactamase (US Pat. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (U.S. Patent Nos. 5,221, 623, 5,683,888, 5,674,713, 5,650,289, 5,843,746) and naturally fluorescent proteins (Tsien, RY (1998) Annu.Rev. Biochem.67 509-44) . The use of chimeras comprising the ligand binding domain (LBD) of the nuclear receptor of interest for a DNA binding domain. 'heterologous (DBD) expands the versatility of cell-based assays by directing the activation of the nuclear receptor in question to define the elements that link DNA recognized by the domain that binds to the defined DNA (see W095 / 18380). This assay expands the utility of cell-based co-transfection assays in cases where the biological response or window of exclusion by using the native DNA domain is not satisfactory. In general, the methodology is similar to that used with the basic co-transfection assay, except that a chimeric construct is used in place of the full-length receptor. Because the full length nuclear receptor, the treatment of cells transfected with an agonist for the nuclear receptor LBD increases the transcriptional activity of the heterologous DNA binding domain that is reflected by an increase in reporter gene expression as described above . Typically, for such chimeric constructs, the domains that bind DNA from defined nuclear receptors or from yeasts or bacterially derived transcriptional regulators such as members of the GAL 4 and Lex A / Umud superfamily are used. A third utility-based assay for separation separation compounds of the present invention is a two-hybrid mammalian assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand, (see example, U.S. Patent Nos. 5,667,973, 5,283,173 and 5,468,614). The basic methodology is to create three plasmid constructs that allow the interaction of the nuclear receptor with the interaction protein to be coupled to a transcriptional reading within a living cell. The first construct is an expression plasmid for expressing a fusion protein comprising the interaction protein or a portion of the protein comprising the interaction domain, fused to a domain that binds to GAL4 DNA. The secondary expression plasmid comprises DNA encoding the nuclear receptor of interest fused to a transcription activation domain such as VP16, and the third construct comprises the reporter plasmid that undertakes a reporter gene with a minimal promoter and sequences that are activated in the upward direction GAL4. Once all three plasmids are introduced into a cell, the domain that binds DNA to GAL4 encoded in the first construct allows specific binding of the fusion protein to the GAL4 sites in the upstream direction of a minimal promoter. However, because the .e.-domain linking AE) N to GAL4 does not typically have transcriptional activation properties in isolation, reporter gene expression occurs only at low levels. In the presence of a ligand, the nuclear receptor-VP16 fusion protein can bind to the fusion protein of the GAL-4 interacting protein producing the VP16 of strong transcriptional activation in close proximity to the GAL4 binding sites and the region of the minimal promoter of the reporter gene. This interaction significantly improves the transcription of the reporter gene that can be measured for different genes _ reporters as described above. Transcription of the reporter gene is then conducted by the interaction of the interaction protein and the nuclear receptor of interest in a ligand-dependent manner.

Any compound that is a candidate for activation of the farnesoid X receptor can be tested by these methods. Generally, compounds are tested in different concentrations to optimize the changes in which receptor activation will be detected and recognized if present. Typically, the assays are performed in triplicate and vary within the experimental error by less than 15%. Each of the experiments is typically repeated three or more times with similar results. The activity of the reporter gene can be conveniently normalized for internal control and the data is plotted as fold activation relative to untreated cells. A positive control compound (agonist) may be included throughout the DMSO as low and high controls for normalization of the test data. Similarly, the antagonist activity can be measured by determining the ability of a compound to competitively inhibit the activity of an agonist. Additionally, compounds and compositions can be evaluated for their ability to increase or decrease the expression of known genes to be modulated by the farnesoid X receptor and other nuclear receptors in vivo, using Northern blotting or Northern blotting, PCR by RT or analysis. of oligonucleotide microarrays to analyze RNA levels, Western blot analysis or "Western blot" can be used to measure the expression of proteins encoded by the farnesoid X receptor targeting genes. Genes that are known to be regulated by the farnesoid X receptor include 7 cholesterol a-hydroxylase (CYP7A1), the enzyme that limits the ratio in the conversion of cholesterol to bile acids, the small heterodimer partner 1 (SHP-1), the export pump of sodium salts of bile (BSEP, ABCB11), protein that exports acids from canalicular bile, polypeptide that cotransports sodium taurocholate (NTCP, SLC10A1) and protein that binds acids from the intestinal bile (I-BABP). Established animal models exist for a variety of diseases of direct relevance to the claimed compounds and these can be used for an additional profile and characterize the claimed compounds. These model systems include diabetic dyslipidemia using Zucker rats (fa / fa) or mice (db / db), hyperlipidemia using mice deficient in alipoprotein E (ApoE ~ / _), diet-induced hyperlipidemia, using mice deficient in the lipoprotein receptor. low density (LDR- / ~) and atherosclerosis using both ApoE ("_) mice and LDL (_, ~) fed a western diet (21% fat, 0. 05% cholesterol). Additionally, the farnesoid X receptor or LXR animal models (eg, agénic mice) can be used to further evaluate the present compound and composition in vivo (see for example, Sinal, et al., Cell, 102: 731-744 (2000 ), Peet, et al., Cell, 93: 693-704 (1998)).

F. Methods of using the compounds and the compositions Methods of using the compounds and compositions provided herein are also provided. The methods include both in vi tro and in vivo uses of the compounds and compositions to alter the activity of the nuclear receptor including the farnesoid X receptor and / or orphan nuclear receptor activity and for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders that are modulated by an activity of the nuclear receptor, which includes the farnesoid X receptor and / or orphan nuclear receptor activity or in which nuclear receptor activity is involved, including the farnesoid X receptor and / or the activity of the orphan nuclear receptor. Such compounds or compositions will typically exhibit the farnesoid X receptor agonist, partial agonist, partial antagonist or antagonist activity in one of the in vitro assays described herein. Methods are provided to alter the activity of the nuclear receptor, include the farnesoid X receptor, and / or orphan nuclear receptor activity, by contacting one or more compounds or compositions provided herein. Methods to reduce plasma cholesterol levels and to indirectly or directly modulate cholesterol metabolism, catabolism, synthesis, absorption are provided. re-absorption, secretion or excretion through the administration of the claimed compounds and compositions provided herein. Methods for reducing the absorption of dietary cholesterol are provided (see for example, International patent application publication No.00 / 40965) using the compounds and compositions. Also provided are methods for increasing the expression of the cassette that binds ATP (ABCA1), thereby increasing the transport of the reverse cholesterol in mammalian cells using the claimed compounds and compositions (see for example, Publication of the international patent application No- WO 00/78972). Methods for reducing plasma triglyceride levels and for directly or indirectly modulating metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion are provided through the administration of the claimed compounds and compositions provided herein. Methods are provided to reduce acid levels of bile and to directly or indirectly modulate bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretion, excretion, or bile acid block size of the bile or composition by administering the claimed compounds and compositions provided herein. The methods of treatment, prevention, • or decrease in one or more symptoms of a disease or disorder that affects cholesterol, triglycerides or bile acid levels or any combination thereof, using the compounds and / or compositions provided herein. Methods are provided for the treatment, prevention or reduction of one or more symptoms of, as well as the treatment of complications of hyperlipidemia, hypercholesterolemia, dyslipidemia and lipodystrophy, comprising the administration of the claimed compounds and compositions to a subject in need of same. The term "hyperlipidemia" refers to the presence of an abnlly high level of lipids in the blood. Hyperlipidemia can appear in at least three ways: (1) hypercholesterolemia, that is, a high LDL cholesterol level (120 mg / dL and above); (2) hypertriglyceridemia, is ecir, a high level of triglycerides; (150 mg / dL and above) and (3) combined hyperlipidemia, that is, a combination of hypercholesterolemia and hypertriglyceridemia. The term "dyslipidemia" refers to abnl levels of lipoproteins in the blood plasma that include both depressed and / or elevated levels of lipoproteins (e.g., high levels of low density lipoprotein, (LDL), very low density lipoproteins). (VLDL) and depressed levels of high density lipoprotein (HDL) (less than 40 mg / dL)). Methods for the treatment, prevention or reduction of one or more symptoms of atherosclerosis, atherosclerotic diseases, events of atherosclerotic diseases and atherosclerotic cardiovascular diseases comprising the administration of the claimed compounds and / or compositions to a subject in need thereof are also provided. . Atherosclerosis is the process in which the deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances are built into the inner lining of an artery. This increase is called a plate. This initially affects the arteries of medium and large size. The hardening of some arteries occurs frequently when people are very old. Plaques can grow large enough to significantly reduce the flow of blood through an artery. However, significant damage to the body can also occur when the walls of the arteries become brittle and rupture. Atherosclerotic plaques that rupture can cause blood clots to fthat can block blood flow or rupture and travel to another part of the body. If it happens that blood clots block a blood vessel that feeds the heart, a heart attack can occur. If the blood clot blocks a blood vessel that feeds the brain, it can lead to a stroke. And if the blood supply to the arms or legs is reduced, difficulty in walking and eventually gangrene may result. Accordingly, atherosclerosis encompasses a range of vascular diseases and conditions that arise as a result of the primary disease modality. Atherosclerotic cardiovascular diseases can be recognized and understood by practicing physicians in the 'Relevant fields of medicine including the following: Restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including stroke Ischemic stroke, dementia of multiple infarcts and peripheral vessel disease including erectile dysfunction.

A compound or composition of the present invention can be administered to prevent or reduce the risk of occurrence, or recurrence when the potential exists, of the coronary heart disease event, a cerebrovascular event, and / or intermittent claudication. It is intended that cases of coronary heart disease include death due to coronary heart disease, myocardial infarction and coronary revascularization procedures. It is intended that cerebrovascular events include ischemic or hemorrhagic attack (also known as strokes) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vascular disease. The term "atherosclerotic disease event" as used herein, is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that a person who has previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists. Additionally, the present invention also provides a method for preventing or reducing the risk of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of a compound or composition of the present invention to a patient at risk for such an event. The patient may already have atherosclerotic disease at the time of administration, or may be at risk of developing it. Risk factors for developing atherosclerotic disease events include increased age (65 and above), male gender, family history of atherosclerotic disease events, high blood cholesterol (especially LDL or higher "bad" cholesterol). at 100 mg / dL), cigarette smoking and exposure to tobacco smoke, high blood pressure, diabetes mellitus, obesity and physical inactivity. In another aspect, the method of this invention also serves to remove cholesterol from tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifested by clinical signs such as angina, lameness, confused sounds, someone who has suffered from a myocardial infarction or transient ischemic attack, or one diagnosed by angiography, sonography or MRI, through the administration of the claimed compounds and composition to a subject who needs it.

The methods of treatment, prevention, or reduction of one or more of the symptoms of diabetes mellitus, as well as treating the complications of diabetes mellitus, (see for example, International Patent Application Publication No. WO 01/82917 ) are also provided by using the compounds and compositions provided herein. Diabetes mellitus, commonly called diabetes, refers to a disease or condition that is generally characterized by metabolic defects in the production and utilization of glucose, which results in failure to maintain adequate blood sugar levels in the body ( see, for example, LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincot-Raven Publishers, Philadelphia, Pa. USA 1996)). In the case of type 2 diabetes, the disease is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects over a wide range of concentrations. This resistance to insulin response results in insufficient insulin activation of glucose uptake, oxidation and storage in the muscle, and inadequate insulin repression of lipolysis in adipose tissue and of production and secretion of glucose in the liver (see, for example, Reaven, GM, J. Basic &Clin Phys. &Pharm. (1998) 9: 387-406 and Flier, J. Ann Rev. Med. (1983) 34: 145-60) . The resulting condition is elevated glucose in the blood, which is called "hyperglycemia." Uncontrolled hyperglycemia is associated with increasing and premature mortality due to an increased risk of microvascular and macrovascular diseases, including retinopathy (disability or loss of vision due to damage to the blood vessel in the eyes); neuropathy (damage to nerves and problems in the feet due to damage to blood vessels to the nervous system); and nephropathy (kidney disease due to damage to the blood vessels in the kidneys), hypertension, cerebrovascular disease and coronary heart disease. Therefore, the control of glucose homeostasis is an important approach for the treatment of diabetes. Methods of treating, preventing, or decreasing one or more of the insensitivity or insulin resistance symptoms as well as treating the insensitivity or insulin resistance complications (see for example, International Patent Application Publication No. WO) 01/82917) are also provided by using the compounds and compositions provided herein. Methods of treating, preventing, or decreasing one or more of the symptoms of hyperglycemia as well as treating the complications of hyperglycemia (see for example, International Patent Application Publication No. WO 01/82917) are also provided by using the compounds and compositions provided herein. Insulin resistance has the hypothesis that it unifies the grouping of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglycerides and decreased HDL cholesterol, and central and general obesity. The association of insulin resistance with glucose intolerance, an increase in plasma triglycerides and a decrease in the concentrations - of high density lipoprotein cholesterol, hypertension, hyperuricemia, smaller low density lipoprotein particles and denser, and higher circulating levels of plasminogen activator inhibitor 1, have been referred to as "Syndrome X" (see, for example, Reaven, GM, Physiol. Rev. (1995) 75: 473-486). Thus, methods of treatment, prevention, or reduction of some disorders related to diabetes, hyperglycemia or insulin resistance including the grouping of the disease states, conditions or disorders constituting the "Syndrome X" are provided. Additionally, the present invention also provides a method for preventing or reducing the risk of developing hyperglycemia, insulin resistance or development of diabetes in a patient, which comprises administering a prophylactically effective amount of a compound or composition of the present invention. to a patient at risk of such an event. The patient may already be obese, (BMI of 30.0 or greater), overweight (BMI from 25.0 to 30.0) or have other risk factors for developing diabetes including age, family history and physical inactivity. In addition, methods for the treatment, prevention, or reduction of one or more symptoms of cholestasis, as well as for the treatment of complications of cholestasis by administering a compound or composition provided herein, are provided herein. Cholestasis is typically caused by factors within the liver (intrahepatic) or outside the liver (extrahepatic) and leads to the accumulation of bile salts, bile pigment bilirubin, and lipids in the blood stream instead of being removed normally. Intrahepatic cholestasis is characterized by a wide blockage of small ducts or by disorders, such as hepatitis, that affect the body's ability to eliminate bile. Intrahepatic cholestasis can also be caused by alcoholic liver disease, primary biliary cirrhosis, cancer that has spread (metastasized) from another part of the body, primary sclerotizing cholangitis, stones in the gallbladder, biliary colic, and acute cholecystitis. It can also happen as a complication of surgery, serious injury, cystic fibrosis, infection or intravenous feeding or drug induction. Cholestasis can also happen as a complication of pregnancy and often develops during the second and third trimesters.

Extrahepatic cholestasis is most commonly caused by choledocholithiasis (stones in the bile duct), benign biliary structures (non-cancerous narrowing of the common duct), cholangiocarcinoma (ductal carcinoma), and pancreatic carcinoma. Extrahepatic cholestasis can occur as a side effect of many medications. Thus, compounds or compositions provided herein may be used for the treatment, prevention, or diminution of one or more symptoms of intrahepatic or extrahepatic cholestasis, including without limitation, biliary artery, obstetric cholestasis, neonatal cholestasis, drug-induced cholestasis, cholestasis. resulting from infection with Hepatitis C, chronic cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary sclerotizing cholangitis (PSC). It is further provided by this invention, methods for treating obesity, as well as treating complications of obesity, by administering a compound or composition of the present invention. The terms "obese" and "obesity" refer to, according to the World Health Organization, a Body Mass Index (BMI) greater than 27.8 kg / m2 for men and 27.3 kg / m2 for women (BMI equals Weight (kg) / height (m2) Obesity is linked to a variety of medical conditions including diabetes and an atherosclerotic disease event (See, for example, Barrett-Conner, E., Epidemol, Rev. (1989) 11: 172-181; and Knowler, et al., Am. J Clin. Nutr. (1991) 53: 1543-1551) In this manner the claimed compounds or compositions that can be used for the treatment of obesity or its complications, and can be identified, formulated, and administered as previously described above.

G. Combination Therapy Combination therapy is also contemplated herein using one or more compounds or compositions provided herein, or a pharmaceutically acceptable derivative thereof, in combination with one or more of the following: antihyperlipidemic agents, HDL elevating agents in plasma, antihypercholesterolemic agents, inhibitors of cholesterol biosynthesis (such as HMG inhibitors) CoA reductase, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rivastatin), inhibitors of acyl-coenzyme A: cholesterol acyltransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (eg cholestyramine or colestipol)), receptor inducers low density lipoprotein, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, 'vitamin B6, vitamin B12, antioxidant vitamins, β-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, inhibitors of aggregation of platelets, fibrinogen receptor antagonists, LXR ao ß agonists, antagonists or partial agonists, aspirin or fibric acid derivatives. The 'compound or composition provided here, or pharmaceutically acceptable derivative thereof, is administered simultaneously with, prior to, or after administration of one or more of the above agents. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided. The combination therapy includes the administration of a simple pharmaceutical dosage formulation, which contains a compound of the present invention and one or more additional active agents, as well as the administration of a compound of the present invention and each active agent in its own separate formulation of pharmaceutical dosage. For example, a farnesoid X agonist, partial agonist, partial antagonist, or antagonist of the present invention and an HMG-CoA reductase inhibitor can be administered to the patient together in a single oral dose composition such as a tablet or capsule. , or each agent is administered in separate oral dose formulations. Where dose formulations are used separately, the compounds described herein and one or more additional active agents can be administered essentially at the same time, that is, concurrently, or at staggered times separately, that is, sequentially; the . Combination therapy is understood to include all of these regimens. An example of combination therapy that modulates, or prevents the onset of symptoms, or associated complications of atherosclerosis, is administered with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL raising agent; an antihypercholesterolemic agent, such as an inhibitor of cholesterol biosynthesis, for example, an inhibitor of hydroxymethylglutaryl (HMG) CoA reductase (also referred to as statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin), an inhibitor of the HMG-CoA synthase, an squalene epoxidase inhibitor, or an inhibitor of squalene synthetase (also known as squalene synthase inhibitor); an inhibitor of acyl-coenzyme A of cholesterol acyltransferase (ACAT), such as melinamide; probucol; nicotinic acid and the salts thereof and niacinamide; inhibitor of cholesterol absorption, such as β-sitoster l; anion exchange resins of bile acid sequestrants, such as cholestyramine, colestipol or dialkylaminoalkyl derivatives of a crosslinked dextran; an inducer of the LDL receptor (low density lipoprotein); fibrates, such as clofibrate, bezafibrate, fenofibrate, and gemfibrizole; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof, such as the HCl salt; vitamin B12 (also known as cyanocobalamin); vitamin B3 (also known as nicotinic acid and niacinamide, supra); anti-oxidant vitamins, such as vitamin C and E and beta carotene; a beta blocker; LXR a or β agonists, antagonists, or partial agonists, an angiotensin II antagonist; an inhibitor of the angiotensin-converting enzyme; and an inhibitor of platelet aggregation, such as fibrinogen receptor antagonists (ie, glycoprotein receptor antagonists Ilb / lIIa fibrinogen) and aspirin. A compound or composition of the present invention is preferably administered with an inhibitor of cholesterol biosynthesis, particularly an inhibitor of HMG-CoA reductase. The term "HMG-CoA reductase inhibitor" is intended to include all pharmaceutically acceptable salt, ester, free acid and lactone forms of compounds having an HMG-CoA reductase inhibitory activity and, therefore, the use of such forms of salts, esters, free acids and lactone are included within the scope of this invention. Other inhibitors of HMG-CoA reductase can be easily identified using assays well known in the art. For example, suitable assays are described or disclosed in the US patent. No. 4,231,938 and WO 84/02131. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (MEVACOR®; see, U.S. Patent No. 4,231,938); simvastatin (ZOCORR; see, U.S. Patent No. 4,444,784); pravastatin sodium (PRAVACHOLR; see, U.S. Patent No. 4,346,227); fluvastatin sodium (LESCOLR; see, U.S. Patent No. 5,354,772); atorvastatin calcium (LIPITORR; see, U.S. Patent No. 5,273,995) and rivastatin (also known as cerivastatin; see, U.S. Patent No. 5,177,080). The structural formulas of these and of additional inhibitors of HMG-CoA reductase that can be used in the methods of the present invention are described on page 87 of M. Yalpani, "Cholesterol Lowering Drugs," Chemistry & Industry, pp. 85-89 (February 5, 1996). In one embodiment, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin. The dose information for the HMG-CoA reductase inhibitors is well known in the art, since several HMG-CoA reductase inhibitors are marketed in the US. In particular, the amount of daily doses of the HMG-CoA reductase inhibitor can be the same or similar to those amounts that are used for the anti-hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR). For example, see edition 50 of the PDR, 1996 (Medical Economics Co); in particular, see on page 216 the heading "Hipolipidemia", sub-heading, "Inhibitors of HMG-CoA Reductase," and the reference pages cited here. Preferably, the amount of oral dose of HMG-CoA reductase inhibitor is from about 1 to 200 mg / day and, more preferably, from about 5 to 160 mg / day. However, the dose amounts will vary depending on the potency of the specific inhibitor of the HMG-CoA reductase used as well as other factors as noted above. An inhibitor of HMG ^ CoA reductase which has a sufficiently large potency can be given in daily doses of sub-milligrams. As examples, the amount of daily dose for simvastatin can be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The amount of daily dose for atorvastatin calcium may be in the range from 1 mg to 160 mg and, more particularly, from 5 mg to 80 mg. Oral administration can be in single or divided doses of two, three or four times a day, although a simple daily dose of the HMG-CoA reductase inhibitor is preferred. Diabetic patients are likely to suffer from the premature development of atherosclerotic disease events and an increasing rate of cardiovascular and peripheral vascular diseases. Hyperlipidemia and dyslipidemia are important precipitation factors for these diseases. See, for example, Wilson, J. et al., (Ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook of Endocrinology, 9a. Edition, (W. B. Sanders Company, Philadelphia, Pa. U. S. A. 1998). Dyslipidemia is characterized by abnormal levels of lipoproteins in blood plasma (eg, high levels of LDL, VLDL and depressed levels of HDL), and has been shown to be one of the major contributors to the increasing incidence of coronary events and deaths among diabetic subjects (see, for example, Joslin, E. Ann. Chim. Med. (1927) 5: 1061-1079). Epidemiological studies since then have confirmed the association and have shown an increase of several in coronary deaths among diabetic subjects, when compared with non-diabetic subjects (see, for example, García, MJ et al., Diabetes (1974) 23: 105-11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997) 5 (4): 294-315). The methods of the present invention can be effectively used in combination with one or more additional active anti-diabetes agents, depending on the desired target therapy (see, for example, Turner, N. et al. Prog. Drug Res. (1998) 51: 33-94; Haffner, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al. (Eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Several studies have investigated the benefits of combination therapies with oral agents (see, for example, Mahler, R., J. Clin Endocrinol, Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28 , Diabetes Care (1998) 21: 87-92; Bardin, CW, (ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby-- Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin. Ther. (1997) 19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; and Iwa oto, Y. et al, Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82 (12A): 3U-17U). These studies indicate that the modulation of hyperlipidemia associated with diabetes can also improve the outcome of diabetic treatment. Thus, another combination therapy claimed herein is suitable for the treatment of diabetes and its symptoms, complications, and related disorders, and includes co-administration of the compounds or compositions provided herein with for example, sulfonylureas (such as chlorpropamide). , tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glinease, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone); and insulin-related sensitizers, such as selective and non-selective activators of PPARα, PPARβ, and PPARα; LXR a or β agonists, antagonists and partial agonists, dehydroepiandrosterone (also referred to as DHEA or its conjugated sulfate ester, DHEA-S04); antiglucocorticoids; TNFa inhibitors; inhibitors of a-glucosidase (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analogue of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as agents assets discussed above for the treatment of atherosclerosis. Another example of combination therapy claimed herein is the co-administration of the compounds or compositions claimed herein provided, with the compounds or compositions for treating obesity or disorders related to obesity, wherein the claimed compounds can be used effectively in combination with, for example, phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine, dexfenfluramine, fentiramine, β3-adrenoceptor agonists; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), LXR a or β agonists, antagonists and partial agonists, and leptins. Other agents used in the treatment of obesity or disorders related to obesity include neuropeptide Y, enterostatin, colecitocinin, bombesin, amylin, histamine H3 receptors, dopamine D receptors, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA). Another example of a claimed combination therapy is the co-administration of the compound or composition claimed herein provided with compounds or compositions for treatment of cholestasis and its symptoms, complications, and related disorders. Such co-administered compounds include for example, Actigall (Ursodeoxycholic acid-UDCA), corticosteroids, anti-infective agents (Rifampin, Rifadin, Rimactan), antiviral agents, Vitamin D, Vitamin A, .phenobarbital, cholestyramine, UV light, antihistamines, antagonists of the . recipient of oral opiates and bisphosphates, for the treatment, prevention, or reduction of one or more symptoms of intrahepatic or extrahepatic cholestasis. The dose information for these agents is well known in the art. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

EXAMPLE 1 PREPARATION OF ETHYL ESTER OF 3, 6, 7, 8-TETRAHYDRO-IMIDAZO [4, 5-D] AZEPINE-4-CARBOXYLIC ACID A mixture of histamine dichlorohydrate (5.52 g, 30mmol), ethyl bromopyruvate (5.OmL, 36mmol), and activated carbon (500mg) in anhydrous EtOH (80mL) was refluxed under nitrogen for 24 hours. After cooling to room temperature, Et3N (30mL) was added, and the mixture was refluxed at 90 ° C for 6 hours. The activated carbon was completely filtered, and the filtrate was concentrated in vacuo. The residue was taken up in CHC13, and washed twice with water, then dried over Na2SO, and evaporated in vacuo. The residual oil was purified by column chromatography on silica gel eluting with hexane-EtOAc (60:40) to give the title compound as a pale yellow solid. ^? - NMR (CDC13): d 7.49 (ÍH, d)), 7.00 (ÍH, s), 6.79 (ÍH, s), 4.85 (ÍH, br s), 4.30 (2H, q), 3.38 (2H, m), 3.06 (2H, m), 1.36 (3H, t); MS (ES): 208 (MH +).

EXAMPLE 2 PREPARATION OF ETHYL ESTER OF THE ACID 6- (4-FLUORO-BENZOYL) 3,6,7,8-TETRAHYDRO-IMIDAZO [4, 5-D] AZEPINE-4-CARBOXYLIC 4-Fluorobenzoyl chloride was added dropwise to a stirred solution of 3,6,7,8-tetrahydro-imidazo [4,5-d] azepine-4-carboxylic acid ethyl ester (Example 1, 60 mg, 0.29 mmol) and Et3N (0.2mL) in dry CH2C12 at 0 ° C under nitrogen. The resulting mixture was allowed to warm to room temperature overnight. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel by eluting with hexane-EtOAc (80:20) to give the title compound as a yellow solid, - "? - NMR. (CDC13 ): d 8.27-8.21 (3H, m), 7.16 (2H, t), 7.00 (IH, s), 5.10 (IH, br s), 4.35 (2H, q), 3.56 (2H, m), 3.14 ( 2H, t), 1.39 (3H, t); MS (ES): 330 (MH +).

EXAMPLE 3 PREPARATION OF ETHYL ESTER OF 6- (3, 4-DIFLUORO-BENZOYL) -5; 6-DIHYDRO-4H-TIENO [2,3-D] AZEPINE-8-CARBOXYLIC ACID A. To a solution of 3-thiophene acetonitrile (5 g, 40.6 mmol) in anhydrous ether (100 mL) was added lithium aluminum hydride (3 g, 81.2 mmol) in portions at 0 ° C under nitrogen. The suspension was stirred for 30 min at 20 ° C and heated to reflux for 2 h with stirring under nitrogen. After cooling, the reaction mixture was quenched with 10% aqueous Rochelle's salt (Yamada, F. et al, Heterocycles, 1998, 49: 451-457). The solid was removed by filtration and washed with ether and DCM. The filtrate was washed with brine and dried over MgSO4. Evaporation of the solvent gave an oil (4.73 g), which was used in the next step without purification. 'H-NMR (CDC13): d 7.27 (ΔH, m), 6.95-7.05 (2H, m), 2.96 (2H, t), 2.78 (2H, t).

• B. The compound from the previous step was used in a manner similar to that described in Example 1 to prepare the ethyl ester of 5,6-dihydro-4H-thieno [2,3-d] azepine-8-carboxylic acid. MS (ES): 224 (MH +).

C. The title compound was prepared in a manner similar to that described in Example 2 by using 5,6-dihydro-4H-thieno [2,3-d] azepine-8-carboxylic acid ethyl ester and sodium chloride. , 4-difluoro-benzoyl. "? -RMN (CDC13): d 8.01 (1H, s), 7.47 (1H, m), 7.36 (1H, m), 7.27 (2H, m), 6.85 (H, d), 4.23 (2H, q), 4.13 (2H , m), 3.15 (2H, t), 1.23 (3H, t). MS (ES): 364 (MH +).

EXAMPLE 4 PREPARATION OF ETHYL 1, 2, 3, 6-TETRAHIDROAZEPINO [4, 5-B] INDOL-5-CARBOXYLATE A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), ethyl 3-bromopyruvate (1.67 mL, 1.2 equiv) and decolorizing mineral carbon (0.5 g) in absolute ethanol was heated to reflux under nitrogen overnight. TEA was added and the reaction mixture was heated to reflux for another 7.5 hours. After cooling, the mineral coal was removed by filtration and washed with ethanol. The filtrate was concentrated under vacuum and diluted with water (20 mL). It was then extracted with EtOAc (3x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. Evaporation of the solvent and recrystallization from DCM-Hexane gave the title compound (1.17g). XH-NMR (CDC13): d 10.49 (HH, br s), 7.79 (1H, d), 7.43 (HH, d), 7.43 (1H, d), 7.06 (2H, m), 5.27 (1H, br s ), 4.29 (2H, q) 3.58 (2H, m), 3.17 (2H, m), 1.36 (3H, t); MS (ES): 257 (MH +).

EXAMPLE 5 PREPARATION OF ETHYL 3- (4-FLUOROBENZOYL) -1, 2, 3, 6-TETRAHYDROAZEPINO [4,5-B] INDOL- 5 -CARBOXYLATE To a solution of ethyl 1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate (Example 4, 52 mg, 0.2 mmol) in DCM was added 4-fluorobenzoyl chloride (36 L, 0.2 mmol) and TEA (56 μL, 0.4 mmol) and the mixture was stirred overnight at 20 ° C. The trisamine resin (50 mg) was added and the suspension was stirred for 2 hours at 20 ° C. The resin was removed by filtration through a Florisil® cartridge. Evaporation of the solvent gave a crude product, which was purified by trituration with methanol to give the title compound (28 mg); XH-NMR (CDC13): d 10.31 (1H, br s), 7.79 (1H, s), 7.41 (2H,), 7.36 (1H, d), 6.90-7.04 (5H, m), 3.99-4.06 (4H , m), 3.06 (2H, t), 1.02 (3H, t); MS (ES): 379 (MH +).

EXAMPLE 6 PREPARATION OF ETHYL ESTER OF THE ACID 3- (4-FLUORO-BENZOYL) 1,2,3,4,5,6,7,8,9, 10-DECAHYDRO-AZEPINO [, 5-B] INDOL-5- CARBOXILICO A solution of ethyl ester of 3- (4-fluoro-benzoyl) -1, 2, 3, 6-tetrahydro-azepino [4, 5-b] ind-5-carboxylic acid (Example 5, 1.3g, 3.4 mmol) in 60mL of glacial acetic acid containing 500mg of Adams catalyst was subjected to hydrogenation for 14 hours at room temperature and under 45 psi (3.16 kg / cm2) of hydrogen. (Boekelheide, V. and Liu, C-T, J. Am. Chem. Soc. 1952, 74, 4920-4922). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by preparative normal phase HPLC by eluting with 40% EtOAc-Hexane. XH-NMR (CDC13): d 7.99 (HH, s), 7.40-7.37 (2H, m), 7.11-7.06 (2H, m), 4.22-4.15 (4H, m), 3. 54 (ÍH, m), 2.75 (1H, m), 2.54-2.45 (2H, m), 2.31 (2H, m), 1.76 (4H, m), 1.61 (2H, m), 1.32 (3H, m); EM (ES): 385 (MH +).

EXAMPLE 7 PREPARATION OF ETHYL ESTER OF THE ACID 3- (4-FLUORO-BENZOYL) -1,2,3,6,7,8, 9, 10-OCTAH? DRO-AZEPINO [4, 5-B] INDOL-5- CARBOXILICO To a solution of ethyl ester of 3- (4-fluoro-benzoyl) -1,2,3,4,5,6,7,8,9, 10-decahydro-azepino [4,5-b] indole -5-carboxylic acid (Example 6, 60 mg, 0.16 mmol) in DCM (2 mL) was added TEA (45 L, 0.32 mmol) and a solution of tert-butyl hypochlorite (19.2 mL, 0.16 mmol) in DCM (1 mL). mL) at 0 ° C and the mixture was stirred for 0.5 h at 0 ° C. Cold water was added to quench the reaction mixture and the aqueous layer was separated and extracted with DCM. The combined organic layer was washed with water and dried over MgSO4. Evaporation of the solvent gave a crude product, which was purified by column chromatography on silica gel, eluting with MeOH-DCM • (1: 19) to give the title compound (6.5 mg) with some of the starting material (27 mg) recovered. ^? - NMR (CDC13: d 10.07 (HH, s), 7.57 (2H, m), 7.52 (HH, s), 7.10 (2H, m), 4.19 (2H, q), 4.07 (2H, t), 2.89 (2H, t), 2.62 (2H, t), 2.43 (2H, t), 1.80 (4H,), 1.19 (3H, t). MS (ES): 383 (MH +).

EXAMPLE 8 A. Preparation of 2- (1-tert-butoxycarbonyl indol-3-yl) propionitrile To a stirred solution of 3-indolyl acetonitrile (3.9 g, 25 mmdl) in DCM (100 mL, anhyd) was added BOC anhydride (6.5 g, 30 mmol), DMAP (3.6 g, 30 mmol) and TEA (4.2 mL, 30 mL). mmol).

After 1 h the reaction mixture was diluted with DCM (100 mL), washed with IN HCl (2 x 50 mL) and brine, then dried (Na2SO4), concentrated and chromatographed (silica gel, 6% EtOAc / Hex) to result (1-tert-butoxycarbonyl indol-3-yl) acetonitrile (5.4 g, 84%) as a pale yellow solid.1H-NMR (CDC13): d 8.17 (ΔI, br d), 7.64 ( 1 H, br s), 7.52 (1 H, br d), 7.38 (1 H, app t), 7.30. (1 H, app t), 3.78 (2H, s), 1.68 (9H, s). To a stirred solution of (1-tert-butoxycarbonyl indol-3-yl) acetonitrile (5.30 g, 20.7 mmol) in THF (20 mL, anhydrous) cooled to -78 ° C was added dropwise to a 1.0 M solution of LiHMDS in THF (21 mL, 21 mmol). After 40 min, the iodomethane (1.3 mL, 21 mmol) was added rapidly, and the reaction mixture was allowed to warm to room temperature. After 15 h the reaction was quenched by the addition of 0.2 N HCl (100 mL) and extracted with Et20 (2 x 100 mL). The combined extracts were washed with brine, dried (Na 2 SO 4), concentrated and worked up by chromatography (silica gel, 6% EtOAc / Hex) to give the title compound (4.0 g, 71%) as a light yellow oil. . XH-NMR (CDC13): d 8.17 (ΔI, br d), 7.60 (2H,), 7.37 (1 H, br d), 7.30 (1 H, app t), 4.10 (1 H, q), 1.76 ( 3H, d), 1.68 (9H, s).

B. Preparation of 2- (lH-indol-3-yl) propylamine To a stirred solution of 2- (1-tert-butoxycarbonyl indol-3-yl) propionitrile (4.00 g, 14.8 mmol) in DCM (10 mL) was added TFA (10 mL) with caution. After lh the reaction was diluted with DCM (40 mL), washed with water (2 x 40 mL) and brine, then dried (Na2SO4), and concentrated under reduced pressure to give 2- (1H-indol-3) il) propionitrile (2.5 g, 99%) as a pale brown solid. ^? - NMR (CDC13): d 8.25 (1H, d), 1. 69 (1 H, s), 7.65 (1 H, d), 7.45 (1 H, app t), 7.37 (1 H, app t), 4.12 (1 H, q), 1.79 (3 H, d). To a stirred suspension of LAH (3.4 g, 90 mmol) in THF (40 mL, anhydrous) cooled to 0 ° C was added a solution of 2- (1H-indol-3-yl) propionitrile (2.5 g, 14.7 mmol) in THF (40 mL, anhydrous). The reaction mixture was allowed to warm to room temperature and then heated to reflux. After 1 h the reaction mixture was cooled to 0 ° C and carefully quenched with wet THF (5-10% H20) until gas evolution was over.

The resulting mixture was filtered through Celite and concentrated to give a brown residue. The filtrate was rinsed with Et20 (100 mL), which was combined with the residue, dried (Na2SO4), and concentrated under reduced pressure to give the title compound (2.1 g, 82%) as an amber yellow oil. ^? - NMR (CDC13): d 8.28 (1 H, br s), 7.61 (1 H, d), 7.36 (1 H, d), 7.16 (1 H, app t), 7.08 (1 H, app t), 6.96 (1 H, br s) , 3.41 (2H, br s), 3. 19 (1H, q), 2.95 (2H, app d), 1.35 (3H, d).

C. Preparation of ethyl 1-methyl-1,2,3,6-tetrahydroazepino [4,5- b] indole-5-carboxylate In a similar manner to Example 1, the title compound was prepared from 2- (1H-indol-3-yl) propylamine and ethyl pyruvate. MS (ESI): 271 (MH +).

D. Preparation of ethyl 3- (4-fluorobenzoyl) -1-methyl-1,2,3,6-tetrahydro-azepino [4,5-b] indole-5-carboxylate In a manner similar to Example 2, the title compound was prepared from ethyl 1-methyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate and 4-fluorobenzoyl chloride. XH-NMR (CDC13): d 10.54 (1H, br s), 7.97 (1H, s), 7.63-7.68 (2H, m), 7.58 (1 H, d), 7.39 (1 H, d), 7.09- 7.23 (4H, m), 5.28 (1H, dd), 4.25- (2H, m), 3.85 (HI, m), 3.18 (HI, d), 1.34 (3H, d), 1.22 (3H, t); MS (ESI): 393 (MH +).

EXAMPLE 9 PREPARATION OF ETHYL 1, 1-DIMETHYL-1, 2, 3, 6-TETRAHYDRO-AZEPINE [4, 5-B] INDOL-5-CARBOXYLATE In a similar manner to Example 8, the title compound was prepared by using 2 equivalents of iodomethane during the alkylation of (1-tert-butoxycarbonyl indol-3-yl) acetonitrile. MS (ESI): 285 (MH +).

EXAMPLE 10 PREPARATION OF ETIL 1, 1-DIMETHYL-3- (4-FLUOROBENZOYL) -1, 2, 3, 6-TETRAHYDRO-AZEPINE [4, 5-B] INDOL-5-CARBOXYLATE As described in Example 2, the title compound was prepared from ethyl 1,1-dimethyl-1,2,3,6-tetrahydro-azepino [4,5-b] indol-5-carboxylate and sodium chloride. -fluorobenzoyl. ^ -NMR (DMSO-d6): d 10.82 (1H, s), 7.76 (1H, d), 7.65 (1H, s), 7.61 (2H, dd), 7.54 (1H, d), 7.35 (2H, app t), 7.09 (1 H, app t), 6.98 (1 H, app t), 4.22 (2H, q), 3.97 (2H, brs), 1.52 (6H, s), 1.17 (3H, t); MS (ESI): 407 (MH +).

EXAMPLE 11 PREPARATION OF ETHYL ESTER OF THE ACID 3- (4-FLUORO-BENZOYL) -1, 1-DIMETHYL-1,2,3,6,7,8,9, 10-OCTAHYDRO-AZEPINO [4, 5-B] INDOL-5- CARBOXILIC A solution of 3- (4-fluoro-benzoyl) -1,1-dimethyl-l, 2,3,6-tetrahydro-azepino [4,5-b] indole-5-carboxylic acid ethyl ester (1.03g) ) in 40 mL of glacial acetic acid containing 370 mg of Adams catalyst was subjected to hydrogenation under atmospheric pressure of hydrogen for 20 hours at room temperature. (Boekelheide, V. and Liu, C-T, J. Am. Chem. Soc. 1952, 74, 4920-4922). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was first purified by column chromatography on silica gel eluting with hexane / DCM and then by preparative HPLC to normal phase on elution with hexane / DCM. The title compound was obtained as yellow solid (64mg). XH-NMR (CDC13): d 10.18 (1H, s), 7.64-7.59 (2H,), 7.41 (H, s), 7.13-7.07 (2H, m ), 4.18 (2H, q), 3.95 (2H, brs), 2.68-2.61 (4H, m), 1.78 (4H, m), 1.39 (6H, S), 1.18 (3H, t); MS (ES): 411 (MH +).

EXAMPLE 12 PREPARATION OF ETHYL ESTER OF THE ACID 6- (3,4-DIFLUORO-BENZOYL) -4,4-DIMETYL-5,6-DIHYDRO-4H-THINENE [2,3-D] AZEPINE- 8 • CARBOXYLIC To a solution of thiophene-3-acetonitrile (6.15 g, 50 mmol) and Mel (12.5 mL, 4 equiv) in DMF (200 L) was added sodium hydride (6 g, 60%, 3 equiv) at 0 ° C. under nitrogen and the reaction mixture was stirred for 3 h at 0 ° C. Then it was quenched with water and extracted with hexane (3x100 mL). The combined organic layer was washed with water and dried over MgSO4. Evaporation of the solvent produced 2-methyl-2-thiophen-3-yl-propionitrile as an oil, which was used in the next step without further purification. - "" H-NMR (CDC13): d 8.02 (1 H, m), 7.35 (1 H, dd), 7.12 (1 H, dd), 2.96 (3 H, s), 2.89 (3 H, s). To a solution of 2-methyl-2-thiophen-3-yl-propionitrile in anhydrous ether (200 mL) was added lithium aluminum hydride. (5.7 g, 3 equiv) at 0 ° C under nitrogen. Stirring was continued for 0.5 h at 20 ° C and 3 h at reflux under nitrogen.

After cooling, it was quenched with 10% Rochelle's aqueous salt (Yamada, F. et al, Heterocycles, 1998, 49: 451-457) and the solid was removed by filtration and washed with ether. The combined filtrate was washed with water and dried over MgSO4. Evaporation of the solvent afforded 2-methyl-2-thiophen-3-yl-propylamine as an oil (4.62 g). XH-NMR (CDC13): d 7.29 (ΔI, dd), 7.03 (1H, dd), 6.99 (1H, dd), 2.74 (2H, s), 1.29 (6H, s). 2-methyl-2-thiophen-3-yl-propylamine was used in a manner similar to that described in Example 1 to prepare the ethyl ester of 4,4-dimethyl-5,6-dihydro-4H-thieno [2] , 3-d] azepino-8-carboxylic acid. MS (ES): 252 (MH +).

The title compound was prepared in a manner similar to that described in Example 2 by using 4,4-dimethyl-5,6-dihydro-4H-thieno [2,3-d] azepino-8-carboxylic acid ethyl ester. . aH-NMR (CDC13): d 7.82 (HH, s), 7.49 (HH, m), 7.37 (1H, m), 7.26 (2H, m), 7.05 (1H, d), 4.23 (2H, q) , 3.95 (2H, t), 1.23 (3H, t). MS (ES): 392 (MH +) EXAMPLE 13 PREPARATION OF DIETILIC ESTER OF THE ACID 6- (3,4-DIFLUORO-BENZOYL) -4,4-DIMETHYL-1,4,5,6-TETRAHYDROPIRROLO [2,3- D] ZEPINE-2, 8-DICARBOXYLIC To a mixture of ethyl pyrrolo-2-carboxylate (8.1 g, 58.3 mmol) and AlCl3 (15.5 g, 2 equiv) in 1,2-dichloroethane-nitromethane (1: 1, 120 mL) was added a, a, -dichloromethyl methyl ether (6.4 mL, 2 equiv) dropwise at -20 ° C. Stirring was continued for 1 h at -20 ° C and the reaction mixture was stored at -20 ° C overnight. It was then emptied on ice, the organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, aqueous NH 4 OH and water and dried over Na 2 SO 4. Evaporation of the solvent afforded ethyl 4-formylpyrrolo-2-carboxylate as a solid (8.8 g, 90%). XH-NMR (CDC13): d 10.40 (HH, s), 8.95 (1H, s), 7.60 (HH, dd), 7.33 (HH, dd), 4.36 (2H, q), 1.39 (3H, t). To a mixture of ethyl 4-formylpyrrolo-2-carboxylate (8.8 g, 52.7 mmol) and dimethylamine (2M in THF, 40 mL, 1.5 equiv) in methanol (60 mL) was added sodium cyanoborohydride (3.3 g, 1 equiv) in portions and the mixture was stirred for 3 h at 20 ° C. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with water and dried over Na2SO4. Evaporation of the solvent yielded a crude product, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1: 9) to give ethyl 4-dimethylaminomethyl-pyrrolo-2-carboxylate as a solid (7.8). g, 76%). MS (ES): 392 (MH +) 197. To a solution of ethyl 4-dimethylaminomethyl-pyrrolo-2-carboxylate (13.45 g, 68.6 mmol) in THF-DCM (1: 1200 mL) was added Mel and the mixture was stirred for 1 h at 20 ° C and stored in the refrigerator overnight. Evaporation of the solvent produced a crude product, which was used in the next step without further purification. To a solution of the above crude in ethanol (120 L) was added sodium cyanide (3.4 g, 5 equiv) and the reaction mixture was heated to reflux for 80 h. After cooling, the solvent was removed and the crude was dissolved in water and extracted with DCM. The combined organic layer was washed with water and dried over MgSO4. Evaporation of the solvent afforded ethyl 4-cyanomethylpyrrolo-2-carboxylate as an oil (9.84 g, 81% over 2 steps). ^ -NMR (CDC13): d 9.30 (HH, s), 6.94 (1H, m), 6.86 (HH, d), 4.30 (2H, q), 3.60 (2H, s), 1.32 (3H, t). To a mixture of ethyl 4-cyanomethylpyrrolo-2-carboxylate (9.84 g, 55.3 mmol), di-tert-butyl dicarbonate (14.5 g, 1.2 equiv) and TEA (11.6 mL, 1.5 equiv) in DCM (250 mL) was added 4-dimethylaminopyridine (0.5 g, 4.4 mmol). and the reaction mixture was stirred for 1 h at 20 ° C and then washed with IN HCl, water, saturated aqueous NaHCO 3, and water. After drying over Na 2 SO, the solvent was evaporated to yield the "2-ethyl ester, 4- (cyano-methyl) -pyrrolo-1,2-dicarboxylic acid 1-tert-butyl ester as an oil (14.2 g. MS (ES): 392 (MH +) 279. To a solution of 2-ethyl ester, 4- (cyanomethyl) -pyrrolo-1,2-dicarboxylic acid 1-tert-butyl ester. (14. 2 g, 51 mmol) and Mel (12.8 mL, 4 equiv) in DMF (250 mL) was added NaH (6 g, 60%, 3 equiv) in portions at -50 ° C. Stirring was continued for 2 h at -5 ° C. The reaction mixture was quenched with brine and extracted with EtOAc three times. The combined organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent produced an oil, which was dissolved in a mixture of TFA-DCM (1: 2.150 mL) and stirring continued for 1 h at 20 ° C. The solvent was removed and the crude was redissolved in DCM. It was then washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent afforded 4- (cyano-dimethyl-methyl) -pyrrolo-2-carboxylic acid ethyl ester as an oil (10.2 g). MS (ES): 392 (MH +) 207. To a solution of 4- (cyano-dimethyl-methyl) -pyrrolo-2-carboxylic acid ethyl ester (10.2 g) in formic acid (80 mL) was added Raney nickel (prepared from a nickel-aluminum alloy (1: 1, 39 g)) and the suspension was heated to reflux with stirring for 1.5 h. Another portion of the catalyst of the same amount was added and the mixture refluxed for another 1.5 h. After cooling, the catalyst was removed by filtration and washed with water and DCM. The aqueous layer was separated and washed with DCM. HCl 1 H was added to the aqueous layer. Evaporation of water afforded 4- (2-amino-1,1-dimethylethyl) -l-1H-pyrrolo-2-carboxylic acid ethyl ester, hydrochloric salt as a solid. MS (ES): (MH + of the free base) 207. The hydrochloride salt of the 4- (2-amino-1,1-dimethyl-ethyl) -lH-pyrrolo-2-carboxylic acid ethyl ester was used in a manner similar to that described in Example 1 in the condensation reaction with ethyl 3-bromopyruvate to prepare 4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo [2, 3-d] diethyl ester ] azepino-2, 8-dicarboxylic acid .XH-NMR (CDC13): d 11.05 (HH, s), 7.76 (HH, d), 6.80 (1H, m), 5.40 (1H, s), 4.26 (4H, m ), 3.14 (2H, t), 1.30 (6H, m). The title compound was prepared - in a manner similar to that described in Example 2 by using 4,4-dimethyl-1,4,6,6-tetrahydro-pyrrolo [2,3-d] azepine-2-diethyl ester , 8-dicarboxylic acid and 3,4-difluoro-benzoyl chloride. ^ -RMN (CDC13): d 11.11 (1 H, s), 7.83 (1 H, s), 7.48 (1 H, m), 7.36 (1 H, m), 6.87 (1 H, d), 4.33 ( 2H, q), 4.24 (2H, q), 3.89 (2H, s), 1.36 (3H, t), 1.33 (6H, s), 1.22 (3H, t). MS (ES): 447 (MH +).

EXAMPLE 14 PREPARATION OF 8-ISOPROPYL ESTHER, 2-ETHYL ESTER OF 6- (3,4-DIFLUORO-BENZOYL) -4,4-DIMETHYL-4, 5, 6-TETRAHYDRO-PYRROLO ESTER [2,3 -D] AZEPINO-2,8-DICARBOXILICO The title compound was prepared in a manner similar to that described in Example 13 by using iso-propyl 3-bromopyruvate in the reaction condensation of the hydrochloride salt of the ethyl ester of 4- (2-amino-1, 1-dimethyl-ethyl) -lH-pyrrolo-2-carboxylic acid to prepare 8-isopropyl ester, 2-ethyl ester of 4,4-dimethyl-1,4,6,6-tetrahydro-pyrrolo [2,3 -d] azepino-2, 8-dicarboxylic acid. MS (ES): 321 (MH +) The title compound was prepared in a manner similar to that described in Example 2 by using 8-isopropyl ester, 2-ethyl ester of 4,4-dimethyl-1,4, 5,6-tetrahydro-pyrrolo [2,3-d] azepino-2, 8-dicarboxylic acid and 3,4-difluoro-benzoyl chloride. ^ -RMN (CDC13): d 11.11 (HH, s), 7.83 (HH, s), 7.48 (1H, m), 7.27 (HH, m), 6.87 (HH, d), 5.10 (1H, m), 4.33 (2H, q), 3.92 ( 2H, s), 1.37 (3H, t), 1. 33 (6H, s), 1.21 (6H, d). MS (ES): 461 (MH +).

EXAMPLE 15 PREPARATION OF 8-ISOPROPYL ESTER, ESTER OF 2-TYPE OF ACID 6- (3,4-DIFLUORO-BENZOIL) -1, 4, 4-TRIMETHYL-1, 4, 5, 6-TETRAHYDRO-PIRRÓLO [2,3-D] AZEPINO-2, S-DICARBOXILICO On one occasion, 4- (cyano-dimethyl-methyl) -l-methyl-pyrrolo-2-carboxylic acid ethyl ester was obtained as a by-product when the ethyl ester of 4- (cyano-dimethyl- methyl) -pyrrolo-2-carboxylic acid was prepared, this mixture was carried to the following reactions up to the preparation of 8-isopropyl ester, 2-ethyl ester of 4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo [2,3-d] azepino-2, 8-dicarboxylic acid as described in Example 13. At this point the 8-isopropyl ester, 2-ethyl ester of 1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrroloic acid [2,3-d] azepino-2, 8-dicarboxylic was isolated from the mixture. MS (ES): 335 (MH '). The title compound was prepared in a manner similar to that described in Example 2 by using 8-isopropyl ester, 2-ethyl ester of 1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrroloic acid. [2, 3-d] azepino-2, 8-dicarboxylic acid and 3,4-difluoro-benzoyl chloride ^ H-NMR (CDC13): d 7.75 (1H, s), 7.43 (H, m), 7.28 (2H , m), 6.86 (HH, d), 5.06 (1H, m), 4.28 (2H, q), 3.87 (2H, s), 3.66 (3H, s), 1.35 (3H, 3), 1.33 (6H, s), 1.21 (6H, d). MS (ES): 475 (MH +).

EXAMPLE 16 TRANSFER OF ENERGY BY RESOLUTION OF FLUORESCENCE RESOLUTION IN TIME (TR-FRET) The TR-FRET assay is carried out by incubating 8 nM of the GST-farnesoid receptor X-LBD (comprising glutathione-S-transferase fused) in structure to the ligand domain of the farnesoid X receptor ligand, (amino acids 244-471 of human farnesoid X receptor)), 8 nM of europium labeled anti-GST antibody (Wallac / PE Life Sciences Cat # AD0064), 16 nM of biotin peptide-SRC-1 [5'-biotin-CPSSHSSLTERHKILHRLLQEGSPS-CONH2], 20 nM of APC-SA [streptavidin conjugated to allophycocyanin] (Wallac / PE Life Sciences, Cat # AD0059A) in buffer of FRET assay ( 20 mM KH2PO4 / K2HP04 (pH 7.3), 150 mM NaCl, 2 mM CHAPS, 2 mM EDTA, 1 mM DTT) in the presence of the test compound (s) for 2-4 hours at room temperature in a room 384 well test plate. The data was collected using a LJL Analyst Analyzer using the standard operating instructions and conditions with readings at the emission wavelengths of 615 nm and 665 nm after a delay of 65 μs and an excitation wavelength of 330 nm .

EXAMPLE 17 CO-TRANSFER ASSAY The basic co-transfection protocol for measuring farnesoid X receptor activity is as follows. Cells CV-1 of the African Green Monkey kidney were plated 24 hours before transfection to achieve approximately 70-80 percent confluence. Cells were transfected with the following expression vectors, CMX-farnesoid receptor X (full length human farnesoid X receptor), CMX-RXRa (full-length human RXR), Lucl2 ((ECREx7-Tk-Luciferase) reporter gene construct of luciferase. (See WO 00/76523, Venkateswaran et al., (2000) J. Biol. Chem. 275 14700-14707.) An expression vector of CMX-β-Galactosidase was used as a transfection control. The transfection reagent used was DOTAP (Boehringer Mannheim) .The cells were incubated with the DOTAP / DNA mixture for 5 hours after which the cells were harvested and plated onto 96-well plates or 384 wells containing the concentration of the test compound The test was allowed to continue for an additional 18-20 hours, after which the cells were used, with lysis buffer (1% triton X 100, 10% glycerol, 5 mM Dithiothreitol, 1 M EGTA, 25 mM Tricine, pH 7.8) and the activity d of luciferase was measured in the presence of the Luciferase assay buffer (0.73 mM ATP, 22.3 M Tricine, 0.11 mM EGTA, 0.55 mM Luciferin, 0.15 M Coenzyme A, 0.5 mM HEPES, 10 mM magnesium sulfate) on a standard luminometer plate reader (PE Biosystems, NorthStar Reader), using the instructions and recommended operating conditions.

RESULTS OF EXAMPLE 18 AND 19 Both the co-transfection assay of the farnesoid receptor X / ECR? X7 (Example 10) and the TR-FRET assay (Example 9) can be used to establish the values ECso / IC5o for potency and activity in percentage or inhibition for efficacy. Efficiency defines the activity of a compound relative to a high control (chenodeoxycholic acid, CDCA) or a low control (DMSO / vehicle).

The dose response curves are generated from an 8 point curve with concentrations that differ by 1/2 LOG units. Each point represents the average of the 4 data wells from a 384-well plate. The curve for the data is generated by using the equation: Y = Fund + (Top-Bottom) / (1 + 10? ((LogEC50-X) * Top Slope)) The EC5o / IC50 is therefore defined as the concentration at which an agonist or antagonist produces a response that is halved between the upper (maximum) and the bottom (baseline) values. The EC5o / IC5o values represented are the averages of at least 3 independent experiments. The determination of the relative efficacy or% control for an agonist is by comparison to the maximum response achieved by the chenodeoxycholic acid that is measured individually in each dose response experiment. For the antagonist assay, CDCA is added to each well of a 384 well plate to produce a response. The% inhibition for each antagonist is therefore a measure of the inhibition of CDCA activity. In this example, 100% inhibition would indicate that the CDCA activity has been reduced to baseline levels, defined as the assay activity in the presence of only DMSO. Most of the compounds described and tested here show activity in at least one of the above assays (EC50 or IC50 less than 10 μM). Most showed activity at or below 1 μM. For example, the following compound showed agonist activity at or less than 1 μM EC50 with more than 100% efficacy when measured by the co-transfection assay: 3- (4-Fluoro-benzoyl) ethyl ester - 1,2,3,6,7,8,9, 10-Octahydro-azepino [4, 5-b] indole-5-carboxylic acid.

The following compound showed agonist activity at or less than 100 nM ECS0 with more than 100% efficacy when measured by the co-transfection assay: 3- (4-Fluoro-benzoyl) -1 ethyl ester, 1-dimethyl-1,2,3,4,5,6,7,8,8,9-decahydro-azepino [4, 5-b] indole-5-carboxylic acid; 3- (4-Fluoro-benzoyl) -1, 1-dimethyl-1,2,3,6,7,8,9,10-octahydro-azepino [4,5-b] indole-3-ethyl ester -carboxylic; 6- (3,4-Difluoro-benzoyl) -4,4-dimethyl-5,6-dihydro-4H-thieno [2,3-d] azepino-8-carboxylic acid ethyl ester; 6- (3,4-Difluoro-benzoyl) -4,4-dimethyl-1,4,6,6-tetrahydro-pyrrolo [2,3-d] azepino-2,8-dicarboxylic acid diethyl ester; 8-isopropyl ester, 2-ethyl ester of 6- (3,4-difluoro-benzoyl) -4,4-dimethyl-1,4,6,6-tetrahydro-pyrrolo [2,3-d] azepine ester -2, 8-dicarboxylic; and 8-isopropyl ester, 6- (3,4-difluoro-benzoyl) -1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrrolo [2, 3-ethyl ester] d] azepino-2, 8-dicarboxylic acid. Since the modifications for those skilled in the art will be apparent, it is intended that this invention be. limit only to the scope of the appended claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (48)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. A compound having the formula (I): characterized in that: X is NR9, 0 or S (0) t (where t is 0 to 2); And it is CR30 or N; Z is CR31 or N; R30 and R31 are each independently selected from the group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, heterocyclylalkyl optionally substituted, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR32, -SR32, N (R33) R34, -N (R33) S (0) 2R23; -N (R35) N (R33) R34, N (R35) N (R33) S (O) 2R23, -C (0) R3S, -C (0) OR32, -C (S) OR32, -C (0) ) SR32, -C (O) N (R33) R34, C (S) N (R33) R34, -C (0) N (R33) S (0) 2R23, -C (S) N (R33) S ( O) 2R23, C (0) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and C (0) N (R35) N (R33) S (O) 2R23; or R30 and R31 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring, optionally substituted cycloalkenyl ring, optionally substituted cycloalkynyl ring, optionally substituted heterocyclyl ring, optionally substituted heteroaryl ring or optionally substituted aryl ring with the exception of substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl; R32, R33, R34, R35 and R35 are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3S are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R3? and R36 are selected as in (a) above, R1 and R2 are each independently selected from a group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl optionally substituted, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -N (R15) R16, -N (R15) S (0) 2R23; N (R17) N (R15) R16, -N (R17) N (R15) S (0) 2R23, -C (0) R18, -C (0) 0R14, C (S) 0R14, -C (0) SR14, -C (0) N (R15) R16,. -C (0) N (R15) S (0) 2R23, C (0) N (R15) N = R1S, -C (0) N (R17) N (R15) R16 and -C (0) N (R17) ) N (R1?) S (O) 2R23; R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl, -C (0) R10, -C ( 0) 0R10, -S (0) 2R10, C (0) N (RX1) R12, -C (0) N (R11) S (0) 2R23, -C (O) N (R13) N (R11) R12 , C (0) N (R13) N (R11) S (0) 2R23, -N (R13) C (O) R10, -N (R13) C (0) N (R11) R12, -N (R13) C (0) N (RX1) S (0) 2R23, -N (R10) C (O) N (R13) N (R1X) R12, N (R10) C (O) N (R13) N (R?: L ) S (O) 2R23, -N (R13) C (0) OR10, -P (0) 0R10 or -P (0) (OR19) OR12; R4", R ?, R6 and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, heterocyclyl optionally substituted, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -S (0) 2R14, -N (R15) R16, -N (R15) S (O) 2R23, -N (R15) C (0) 2R23, -C (0) R18, -C (0) OR2 °, -C (O) N (R2X) R22, C (0) N (R2X) S (0) 2R23; -C (O) N (R2) N (R2X) R22 and C (0) N (R24) N (R2X) S (0) 2R23; or R6 and R7 together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or R6 and R7, together with the carbon atom to which they are bonded, form an optionally substituted exocyclic double bond, and R4 and R? they are as described above; or R4 and R5 together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or R4 and R5, together with the carbon atom to which they are attached, form optionally substituted exocyclic double bond, and R6 and R7 are as described above; or R4 and R5, or R4 and R6, or R4 and R7, or R? and R6, or R5 and R7, or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted heterocyclyl ring, an optionally substituted cycloalkenyl ring or together form a double bond , and the others of R4, R5, R6 and R7 are as described above; or R4 and R5, together with the carbon atom to which they are attached, and R5 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted heterocyclyl ring or a cycloalkenyl ring optionally substituted. R9 is hydrogen, optionally substituted alkyl, C (0) .R18, -C (0) OR20 0-S (0) 2R23; Rxo, Rxx, R12, R13 and R19 are selected as in (a) or (b) as follows: (a) R10, R11, R12, R13 and R19 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R11 and R12 or R12 - and R19, together with the atoms to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and the others of R10, R11, R12, R13 and R19 are selected as in (a), above; R14, R15, R1, R7 and R are selected as in (a) 'or (b) as follows: (a) R14, R15, R1S, R17 and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R15 and R1S, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R14, R15, R16, R17 and R18 are selected as in (a) above; R20, R21, R22 and R24 are selected as in (a) or (b) as follows: (a) R20, R21, R22 and R24 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl optionally substituted, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R21 and R22, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R20, R21, R22 and R24 are selected as (a) above; R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; each of R1-R24 and R30-R3d, when substituted, are substituted with one or more substituents, each independently selected from Q1; each Q1 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing from 1 to 2 double bonds, alkynyl containing from 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl ,. aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, -OR70, -SR70, -R60-, C (J) R71, -R60-N (R70) C (J) R71 , -OC (0) R71, -R60-N (R75) (R7S), -N + (R77) 3, -P (R78) 2, - P (0) (R78) 2, -0P (0) (R78) ) 2, -N (R70) S (O) 2R71, -S (0) 2R71, -S (0) R82, -OS (0) R83, -OS (0) 2R83 or -SY (R83) 3; two Q1 groups, which substitute atoms in a 1,2 or 1,3 configuration, together with the carbon atoms to which they join form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; or each Q1 is independently substituted or unsubstituted with one or more substituents each independently selected from Q2; each Q2 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing from 1 to 2 double bonds, alkynyl containing from 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, -OR70, -SR70, -R60-C (J) R71, -R60- N (R70) C (J) R71, -OC (0) R71, -R60-N (R75) (R76), -N + (R77) 3, -P (R78) 2, - P (0) (R78) 2, -OP (O) (R78) 2, -N (R70) S (0) 2R71, -S (0) 2R71, -S (0) R82, -OS (0) R83, -OS (0) 2R83 or -Yes (R83) 3; two Q2 groups, which replace atoms in a 1,2 or 1,3 configuration, together with the carbon atoms to which they are attached form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; each J is independently O, S or -NR70; each R60 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroalkyl, -OR72, or -N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring, - R75 and R7S are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R76, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; each R77 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R78 is alkyl, heteroaryl, heterocyclyl, aryl, -OR79 or -N (R80) R81; R79 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R80 and R81 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R80 and R81, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; R82 is alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl or -OR83; and each R83 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; as a single isomer, a mixture of isomers, or as a racemic mixture of isomers; or as a solvate or polymorph; or as a prodrug; or as a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that: R1 is -C (0) R18, -C (0) 0R14, -C (S) 0R14, -C (0) SR14, C (0) N (R15) R16, -C (0) N (R15) S (0) 2R23, -C (O) N (R15) N = R16, C (0) N (R17) N (R1S) R1S or -C (0) N (R17) N (R15) S (0) 2R23; wherein R14, R15, R16, R17 and R23 are described in claim 1.

3. The compound according to claim 2, characterized in that R3 is -C (0) R10, -C (0) OR10, -S (0) 2R10 or -C (0) N (R1X) R12; wherein R10, R11 and R12 are described in claim 1.

4. The compound according to claim 3, characterized in that R 2 is hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl.

5. The compound according to claim 4, characterized in that R4, R5, R6 and R7 are selected from a), b), c), d), e), f), g), h) and i) below: a R4 and R5 are each independently hydrogen or halo and R6 and R7 are optionally substituted alkyl, - b) Rs and R7 are each independently hydrogen or halo and R4 and R5 are optionally substituted alkyl; c) R4, R5, Rs and R7. each optionally substituted alkyl; d) R4 and R5 are each independently hydrogen or halo and R6 and R7, together with the carbon to which they are linked, independently form an optionally substituted cycloalkyl or optionally substituted cycloalkenyl ring. e) R4 and R5 are optionally substituted alkyl, and Rs and "R7 together with the carbon to the carbon are linked, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl f) R4 and R5, together with the carbon to which they are attached, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl ring and Rd and R7 are each independently hydrogen or halo; g) R4 and R5, together with the carbon to which they are attached, independently form an optionally substituted hydroalkyl ring or optionally substituted cycloalkenyl ring and R6 and R7 are optionally substituted alkyl; h) R4 and R5, together with the carbon to which they are linked, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl ring and R6 and R7, together with the carbon to which they are bonded, independently form a cycloalkyl ring optionally substituted or optionally substituted cycloalkenyl ring; and i) R4, R5, R6 and R7 are each independently hydrogen or halo.

6. The compound according to claim 5, characterized in that: Y is CR30; and R 30 is halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, heteroaralkyl optionally replaced,. -OR32, -SR32, -N (R3) R34, -N (R33) S (O) 2R23; N (R35) N (R33) R34, -N (R35) N (R33) S (0) 2R23, -C (0) R3e, -C (0) OR32, C (S) OR32, -C (0) SR32, -C (0) N (R33) R34, -C (S) N (R33) R34, C (0) N (R33) S (0) 2R23, -C (S) N (R33) S (0 ) 2R23, -C (O) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 or -C (O) N (R35) N (R33) S (O) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R36 are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3e are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R3? and R36 are selected as in (a) above.

7. The compound according to claim 6, which "has the formula (II): 00 or a pharmaceutically acceptable derivative thereof, characterized in that: R1 is -C (0) 0R14; -C (S) 0R14, -C (0) SR14, -C (0) N (R15) R1S, -C (0) N (R15) S (0) 2R23, -C (0) N (Rx5) N = R16, -C (0) N (R17) N (R15) R15 and -C (0) N (R17) N (R15) S (O) 2R23; R2 is hydrogen, halo or optionally substituted alkyl; R3 is -C (0) Rxo; R4 and R5 are each independently hydrogen or halo; or R4 and Rs are each optionally substituted alkyl; R6 and R7 are each independently hydrogen or halo; R6 and R7 are each optionally substituted alkyl; or R6 and R7 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl ring or an optionally substituted cycloalkenyl ring; R9 is hydrogen, optionally substituted alkyl, C (0) R18, or -S (0) 2R23; R10 is an optionally substituted aryl or an optionally substituted heteroaryl; R14, R15, Rx, R17 and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally heteroaralkyl replaced; R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and R 30 is halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, heteroaralkyl optionally substituted, -OR32, -SR32, -N (R33) R34, -N (R33) S (0) 2R23; N (R35) N (R33) R34, -N (R35) N (R33) S (0) 2R23, -C (0) R36, -C (0) OR32, -C (S) OR32, -C (0) ) SR32, -C (0) N (R33) R34, -C (S) N (R33) R34, C (0) N (R33) S (O) 2R23, -C (S) N (R33) S ( 0) 2R23, -C (0) N (R35) N (R33) R3C (S) N (R35) N (R33) R34 or -C (O) N (R35) N (R33) S (0 ) 2R23.

8. The compound according to claim 7, characterized in that: R4, R5, Rs and R7 are each independently hydrogen or halo; and R30 is selected from the group consisting of hydrogen, halo, -C (0) R36, -C (0) OR32, -C (S) OR32, -C (0) SR32, -C (0) N (R33) R34, -C (S) N (R33) R34, -C (0) N (R33) S (0) 2R23, -C (S) N (R33) S (O) 2R23, C (0) N (R35) ) N (R33) R34, -C (S) N (R35) N (R33) R34 and C (0) N (R35) N (R33) S (0) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R36 are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R36 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R36 are selected as in (a) above.

9. The compound according to claim 8, characterized in that the compound is ethyl ester of 6- (4-fluoro-benzoyl) -3,6,7,8-tetrahydro-imidazo [4,5-d] azepino-4 acid. -carboxylic

10. The compound according to claim 7, characterized in that: R4 and R5 are each independently hydrogen or halo; and R6 and R7 are optionally substituted alkyl; or R6 and R7, together with the carbon to which they are bonded, independently form an optionally substituted cycloalkyl ring.

11. The compound according to claim 10, characterized in that R2 is hydrogen, halo or optionally substituted alkyl; and R9 is hydrogen. '25

12. The compound according to claim 11, characterized in that R30 is selected from the group consisting of -C (0) R36, -C (0) OR32, -C (S) OR32, -C (0) SR32, C (0) ) N (R33) R34, -C (S) N (R33) R34, -C (0) N (R33) S (O) 2R23, C (S) N (R33) S (0) 2R23, -C ( 0) N (R3S) N (R33) R34, -C (S) N (R35) N (R33) R34 and -C (O) N (R35) N (R33) S (O) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R3S are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R36 are each independently hydrogen, optionally substituted alkyl, alkenyl optionally substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R3S are selected as in (a) above.

13. The compound according to claim 12, characterized in that Rx is -C (0) OCH2CH3, -C (0) 0CH3, C (0) 0CH (CH3) 2, -C (0) 0H, -C (O) 0CH2CH2CH3 , -C (0) NHCH3, C (0) NHCH2CH3, -C (0) NHCH (CH3) 2, -C (O) H (cyclopropyl), -C (0) NH (cyclopentyl), -C (O) NCH (CH3) (CH2CH3) or -C (0) N (CH3) (cyclopropyl).

14. The compound according to claim 6, characterized in that: Z is CR31; and R3X is independently selected from a group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally aralkyl substituted, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR32, -SR32, -N (R33) R34, -N (R33) S (0) 2R23; -N (R35) N (R33) R34, -N (R35) N (R33) S (0) 2R23, -C (0) R3e, -C (0) 0R32, -C (S) OR32, -C ( 0) SR32, -C (0) N (R33) R34, -C (S) N (R33) R34, -C (O) N (R33) S (0) 2R23, -C (S) N (R33) S (0) 2R23, -C (O) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and -C (O) N (R35) N (R33) S (O) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R36 are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3S are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl,. optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or - (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R36 are selected as in (a) above.

15. The compound according to claim 14, characterized in that: Z is CR31; and R31 is independently selected from a group consisting of optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, -C (0) R3S, -C (0) OR32, - C (S) OR32, -C (0) SR32, -C (0) N (R33) R34, -C (S) N (R33) R34, -C (0) N (R33) S (O) 2R23, -C (S) N (R33) S (0) 2R23, -C (0) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and -C (O) N (R35) N (R33) S (0) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroalkyl; and wherein R32, R33, R34, R35 and R36 are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3S are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R36 are selected as in (a) above.

16. The compound according to claim 14, characterized in that X is 0 or S (0) t (where t is 0 to 2).

17. The compound according to claim 16, characterized in that R4, R5, R6 and R7 are each independently hydrogen or halo; and R30 is selected from the group consisting of hydrogen, halo, -C (0) R36, -C (0) OR32, -C (S) OR32, -C (0) SR32, -C (O) N (R33) R34, -C (S) N (R33) R34, -C (0) N (R33) S (0) 2R23, -C (S) N (R33) S (O) 2R23, C (0) N (R35) ) N (R33) R34, -C (S) N (R35) N (R33) R34 and C (O) N (R35) N (R33) S (O) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R3S are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R36 are each independently hydrogen, optionally substituted alkyl, alkenyl optionally substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R3S are selected as in (a) above.

18. The compound according to claim 17, characterized in that the compound is ethyl ester of 6- (3,4-difluoro-benzoyl) -5,6-dihydro-4H-thieno [2,3-d] azepino-8 acid. - carboxylic.

19. The compound according to claim 16, characterized in that: R4 and R5 are each independently hydrogen or halo; and Re and R7 are optionally substituted alkyl; or R6 and R7, together with the carbon to which they are bonded, independently form an optionally substituted cycloalkyl ring.

20. The compound in accordance with the claim 19, characterized in that: R2 is hydrogen, halo or optionally substituted alkyl; and R9 is hydrogen.

21. The compound in accordance with the claim 20, characterized in that R30 is selected from the group consisting of -C (0) R3d, -C (0) 0R32, -C (S) 0R32, -C (0) SR32, C (0) N (R33) R34, -C (S) N (R33) R34, -C (0) N (R33) S (0) 2R23, C (S) N (R33) S (0) 2R23, -C (0) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and -C (0) N (R35) N (R33) S (O) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R3d are selected as in (a) or "(b) as follows: (a) R32, R33, R34, R35 and R3e are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, aralkyl optionally substituted, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R35 are selected as in (a) above.

22. The compound according to claim 21, characterized in that Rx is -C (O) OCH 2 CH 3, -C (0) OCH 3, C (O) OCH (CH 3) 2, -C (0) OH, -C (O) OCH 2 CH 2 CH 3 / -C (0) NHCH3, C (0) NHCH2CH3, -C (0) NHCH (CH3) 2, -C (0) NH (cyclopropyl), -C (0) NH (cyclopentyl), -C (O) NCH (CH3) (CH2CH3) • or -C (0) N (CH3) (cyclopropyl); and R3 is -C (0) R10 wherein R10 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted aralkyl.

23. The compound according to claim 22, characterized in that it is 6- (3,4-difluoro-benzoyl) -4,4-dimethyl-5,6-dihydro-4H-thieno [2,3-d] ethyl ester. ] azepino-8-carboxylic; or

24. The compound according to claim 14, characterized in that X is NR9; R9 is hydrogen, optionally substituted alkyl, -C (0) R18 or -S (0) 2R23; and R18 and R23 each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.

25. The compound according to claim 24, characterized in that: R4 and R5 are each independently hydrogen or halo; and R6 and R7 are optionally substituted alkyl; or Rd and R7, together with the carbon to which they are attached, independently form an optionally substituted cycloalkyl ring.

26. The compound according to claim 25 characterized in that: R 2 is hydrogen, halo or optionally substituted alkyl; and R9 is hydrogen.

27. The compound according to claim 26, characterized in that R30 is selected from the group consisting of -C (0) R3e, -C (0) OR32, -C (S) OR32, -C (0) SR32, C (0) ) N (R33) R34, -C (S) N (R33) R34, -C (0) N (R33) S (O) 2R23, C (S) N (R33) S (0) 2R23, -C ( 0) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and -C (0) N (R35) N (R33) S (0) 2R23; wherein R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, "optionally substituted heteroaryl, or optionally substituted heteroaralkyl, and wherein R32, R33, R34, R35 and R3d are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3d are each one independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others-of R32, R33, R34, R35 and R3d are select as in (a) above.

28. The compound in accordance with the claim 27, characterized in that R1 is -C (O) OCH2CH3, -C (0) OCH3, C (O) OCH (CH3) 2, -C (0) OH, -C (0) OCH2CH2CH3, -C (0) NHCH3 , C (0) NHCH2CH3, -C (0) NHCH (CH3) 2, -C (O) NH (cyclopropyl), -C (0) NH (cyclopentyl), -C (O) NCH (CH3) (CH2CH3) or C (O) N (CH3) (cyclopropyl); and R3 is -C (0) R10 wherein R10 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted aralkyl.

29. The compound in accordance with the claim 28, characterized in that it is selected from the group consisting of: diethyl ester of 6- (3,4-difluoro-benzoyl) -4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo [2,3] d] azepino-2,8-dicarboxylic; and 8-isopropyl ester, 2-ethyl ester of 6- (3,4-difluoro-benzoyl) -4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo [2,3-d] azepino-2, 8-dicarboxylic.

30. The compound according to claim 29, characterized in that: R4, R5, Rd and R7 are each independently hydrogen or halo; and R30 is selected from the group consisting of hydrogen, halo, -C (0) R3d, -C ('0) 0R32, -C (S) OR32, -C (0) SR32, -C (O) N (R33) ) R34, -C (S) N (R33) R34, -C (0) N (R33) S (0) 2R23, -C (S) N (R33) S (0) 2R23, C (0) N ( R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and C (0) N (R35) N (R33) S (0) 2R23; wherein R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and wherein R32, R33, R34, R35 and R3d are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3d are each independently hydrogen, optionally substituted alkyl, alkenyl optionally substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R3d are selected as in (a) above.

31. The compound according to claim. 30, characterized in that it is 8-isopropyl ester, 2-ethyl ester of 6- (3,4-difluoro-benzoyl) -1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrrolo [ 2,3-d] azepino-2, 8-dicarboxylic acid.

32. The compound according to claim 5, characterized in that: Y is CR30; . Z is CR31; and R30 and R31 together with the carbon atoms to which they are attached, form an optionally substituted cycloalkenyl ring, optionally substituted cycloalkenyl ring, optionally substituted cycloalkynyl ring, optionally substituted heterocyclyl ring, optionally substituted heteroaryl ring or optionally substituted aryl, with the exception of substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl.

33. The compound according to claim 32, characterized in that the optionally substituted cycloalkyl ring is optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl or optionally substituted cyclooctyl.

34. A compound having the formula (V): - or a pharmaceutically acceptable derivative thereof, characterized in that: n is 0 to 8; R1 and R2 are each independently selected from a group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -N (R15) R16, -N (R15) S (O) 2R23; N (R17) N (R15) Rld, -N (R17) N (R15) S (0) 2R23, -C (0) R18, -C (0) OR14, C (S) OR14, -C (0) SR14, -C (0) N (R15) Rld, -C (0) N (R15) S (O) 2R23, C (0) N (R15) N = Rld, -C (0) N (R17) N (R15) Rld and -C (O) N (R17) N (R15) S (O) 2R23; R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl, -C (0) R10, -C ( 0) OR10, -S (0) 2R10, -C (0) N (Ru) R12, -C (0) N (R11) S (0) 2R23, -C (O) N (R13) N (R11) R12, C (0) N (RX3) N (RX1) S (0) 2R23, -N (R13) C (0) R10, -N (R13) C (0) N (R11) R12, -N (R13) ) C (0) N (R11) S (0) 2R23, -N (R10) C (O) N (R13) N (R1X) R12, N (RX0) C (O) N (RX3) N (Rxx) S (O) 2R23, -N (R13) C (O) OR10, -P (0) 0R10, or -P (0) (0R19) 0R12; R4, R5, R6 and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -0R14, -SR14, -S (0) 2R14, -N (R15) Rld, -N (R1?) S (O) 2R23, -N (R15) C (0) R23 , -C (0) R18, -C (O) OR20 -C (O) N (R21) R22, '-C (0) N (R1) S (0) 2R23; -C (O) N (R24) N (R21) R22 and C (0) N (R24) N (R21) S (0) 2R23; or R4 and R5, or R4 and R6, or R4 and R7, or R5 and R6, or R5 and R7, or .Rd and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted heterocyclyl ring, an optionally substituted cycloalkenyl ring or together form a double bond, and the others of R4, R5, Rd and R7 are as described above; or Rd and R7 together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or Rd and R7, together with the carbon atom to which they are attached, form an optionally substituted exocyclic double bond, and R4 and R5 are as described above; R9 is hydrogen, optionally substituted alkyl, C (0) R18 or -S (0) 2R23; R10, R11, R12, R13 and R19 are selected as in (a) or (b) as follows: (a) R10, R11, R12, R13 and R19 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R11 and R12 or R12 and R19, together with the atoms to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and the others of RX0, R11, R12, R13 and R19 are selected as in (a), above; R14, R15, Rld, R17 and R18 are selected as in (a) or (b) as follows: (a) R14, R15, Rld, R17 and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R15 and Rld, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R14, R15, Rld, R17 and R18 are selected as in (a) above; R20, R21, R22 and R24 are selected as in (a) or (b) as follows: (a) R20, R21, R22 and R24 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl optionally substituted, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R21 and R22, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R20, R21, R22 and R24 are selected as (a) above; R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; - each of Rx-R24, when substituted, are substituted with one or more substituents, each independently selected from Q1; each Q1 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing from 1 to 2 double bonds, alkynyl containing from 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, -OR70, -SR70, -Rd0, -C (J) R71, -Rd0 -N (R70) C (J) R71, -OC (0) R71, -Rd0-N (R75) (R7d), -N + (R77) 3, -P (R78) 2, - P (0) (R78) ) 2, -0P (0) (R78) 2, -N (R70) S (O) 2R71, -S (0) 2R71, -S (0) R82, -OS (0) R83, -OS (0) 2R83 or -Si (R83) 3; two groups Q1, which replace atoms in a 1,2 or 1,3 configuration, together with the carbon atoms to which they are attached form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; or each Q1 is independently substituted or unsubstituted with one or more substituents each independently selected from Q2; each Q2 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing from 1 to 2 double bonds, alkynyl containing from 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halo-sulfonyl, -OR70, -SR70, -Rd0-C (J) R71, -Rd0- N (R70) C (J) R71, -0C (0) R71, -Rd0-N (R75) (R7d), -N + (R77) 3, -P (R78) 2, -P (0) (R78) 2, -OP (O) (R78) 2, -N (R70) S (O) 2R71, -S (0) 2R71, -S (0) R82, -OS (0) R83, -OS (0) 2R83 or -YES (R83) 3; two Q2 groups, which substitute atoms in a 1.2 or 1.3 configuration, together with the carbon atoms to which they join form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; each J is independently O, S or -NR70; each RS0 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R7X is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroaralkyl, -OR72 or -N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; R7? and R76 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R7d, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; each R77 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R78 is alkyl, heteroaryl, heterocyclyl, aryl, -OR79 or -N (R80) R81; R79 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R80 and R81 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R80 and R81, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; R82 is alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl or -OR83; and each R83 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl.

35. The compound according to claim 34, characterized in that: R3 is -C (0) R10; wherein R10 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted aralkyl.

36. The compound according to claim 35, characterized in that: R1 is -C (0) R18, -C (0) 0R14 or -C (O) N (R15) R16, wherein R14 and R15 are optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, Rld is hydrogen, and R13 is optionally substituted alkyl.

37. The compound according to claim 36, characterized in that: R 2 is halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally "aralkyl" substituted or optionally substituted heteroaralkyl.

38. The compound according to claim 37, characterized in that: R2 is hydrogen, halo or optionally substituted alkyl; and: R9 is hydrogen or optionally substituted alkyl.

39. The compound according to claim 38, characterized in that R4, R5, Rd and R7 are selected from a), b), c), d), e), f), g) and h) below: a) R4 and R5 are each independently hydrogen or halo and R6 and R7 are optionally substituted alkyl; b) R6 and R7 are each independently hydrogen or halo and R4 and R? they are optionally substituted alkyl; c) R4, R5, Rd and R7 are each optionally substituted alkyl; d) R4 and R5 are each independently hydrogen or halo and R6 and R7, together with the carbon to which they are linked, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl ring. e) -R4 and R5 are optionally substituted alkyl and Rd and R7, together with the carbon to which they are attached, independently form an optionally substituted cycloalkyl or optionally substituted cycloalkenyl ring f) R4 and R ?, together with the carbon to which they bind, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl ring and R6 and R7 are each independently hydrogen or halo; g) R4 and R5, together with the carbon to which they are linked, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkylene ring and Rd and R7 are optionally substituted alkyl; h) R4 and R5, together with the carbon to which they are bonded, independently form an optionally substituted cycloalkyl ring or optionally substituted cycloalkenyl ring and Rd and R7, together with the carbon to which they are bonded, independently form a cycloalkyl ring optionally substituted or optionally substituted cycloalkenyl ring, and i) R4, R5, Rd and R7 are each independently hydrogen or halo.

40. The compound according to claim 39, characterized in that: R4 and R5 are each independently hydrogen or halo; and R6 and R7 are optionally substituted alkyl; or Rd and R7, together with the carbon to which they are attached, independently form an optionally substituted cycloalkyl ring.

41. The compound in accordance with the claim 40, characterized in that: R2 is hydrogen, halo or optionally substituted alkyl; and R-9 is hydrogen.

42. The compound in accordance with the claim 41, characterized in that R1 is -C (O) OCH2CH3, -C (0) OCH3, C (O) OCH (CH3) 2, -C (0) OH, -C (O) OCH2CH2CH3 ', -C (0) NHCH3, C (0) NHCH2CH3, -C (O) NHCH (CH3) 2, -C (O) NH (cyclopropyl), -C (0) NH (cyclopentyl), -C (O) NCH (CH3) (CH2CH3) or C (0) N (CH3) (cyclopropyl); and R3 is -C (0) R10 wherein R10 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted aralkyl.

43. The compound in accordance with the claim 42, characterized in that it is ethyl ester of 3- (4-fluoro-benzoyl) -1, 1-dimethyl-l, 2, 3, 6,7,8,9, 10-octahydro-azepino [4, 5] b] indole-5-carboxylic acid.

44. The compound according to claim 39, characterized in that R4, R5, R6 and R7 are each independently hydrogen or halo.

45. The compound according to claim 44, characterized in that it is ethyl ester of 3- (4-fluoro-benzoyl) -1,2,3,4,5,6,7,8,9, 10-decahydro-azepine. [4, 5-b] indole-5-carboxylic acid or ethyl ester of 3- (4-fluoro-benzoyl) -1, 2, 3, 6, 7, 8,9, 10-octahydro-azepino [4, 5-b] indole-5-carboxylic acid.

46. A pharmaceutical composition characterized in that it comprises a compound of formula (I): X is NR9, O or S (O) t (where t is 0 to 2); And it is CR30 or N; Z is CR31 or N; R30 and R31 are each independently selected from the group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, aryl optionally. substituted, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR32, -SR32, N (R33) R34, -N (R33) S ( ) 2R23; -N (R35) N (R33) R34, N (R35) N (R33) S (0) 2R23, -C (0) R3d, -C (0) OR32, -C (S) 0R32, -C (0) ) SR32, -C (O) N (R33) R34, C (S) N (R33) R34, -C (O) N (R33) S (0) 2R23, -C (S) N (R33) S ( O) 2R23, C (0) N (R35) N (R33) R34, -C (S) N (R35) N (R33) R34 and C (0) N (R35) N (R33) S (0) 2R23; or R30 and R31 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring, optionally substituted cycloalkenyl ring, optionally substituted cycloalkynyl ring, optionally substituted heterocyclyl ring, optionally substituted heteroaryl ring or optionally substituted aryl ring with the exception of substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl; R32, R33, R34, R35 and R3d are selected as in (a) or (b) as follows: (a) R32, R33, R34, R35 and R3S are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R32, R33, R34, R35 and R3d are selected as (a) above, R1 and R2 are each independently selected from a group consisting of halo, hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl , optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -N (R15) Rld, -N (R15) S (O) 2R23; N (Rx7) N (RX5) RXd, -N (RX7) N (RX5) S (0) 2R23, -C (0) R18, -C (0) OR14, C (S, OR14, -C (0) SR14, -C (0) N (R15) R16, -C (0) N (R15) S (O) 2R23, C (0) (R15) N = Rld, -C (0) N (R17) N (R15) Rld and -C (0) N (R17) N (Rxs) S (O) 2R23; R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl, -C (0) R10, -C ( 0) OR10, -S (0) 2R10, -C (0) N (R1: L) R12, -C (0) N (R1X) S (0) 2R23, -C (O) N (R13) N ( Rlx) R12, C (0) N (R13) N (Rlx) S (0) 2R23, -N (R13) C (0) RX0, -N (R13) C (0) N (R11) R12, -N (R13) C (0) N (R11) S (0) 2R23, -N (R10) C (O) N (R13) N (R11) R12, N (10) C (O) N (R13) N ( R11) S (O) 2R23, -N (R13) C (O) OR10, -P (O) OR10 or -P (O) (OR19) OR12; R4, R5, Rd and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -OR14, -SR14, -S (0) 2R14, -N (Rls) Rld, -N (R15) S (0) 2R23, -N (R15) C (0) 2R23, -C (0) R18, -C (0) 0R20, -C (0) N (R21) R22, C (0) N (R21) S (0) 2R23; -C (O) N (R24) N (R21) R22 and C (0) N (R24) N (R21) S (0) 2R23; or RS and R7 together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or Rd and R7, together with the carbon atom to which they are bonded, form an optionally substituted exocyclic double bond, and R4 and R5 are as described above; or R4 and R5 together form an optionally substituted oxo, thioxo, imino, optionally substituted oxime or an optionally substituted hydrazone, or R4 and R5, together with the carbon atom to which they are attached, form optionally substituted exocyclic double bond, and Rd and R7 are as described above; or R4 and R5, or R4 and Rd, or R4 and R7, or R5 and R6, or R5 and R7, or Rd and R7, together with the carbon atom to which they are bonded, form an optionally substituted cycloalkyl ring, ring of optionally substituted heterocyclyl, an optionally substituted cycloalkenyl ring or together form a double bond, and the others of R4, R5, Rd and R7 are as described above; or R4 and R5, together with the carbon atom to which they are bonded, and Rd and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl ring, optionally substituted heterocyclyl ring or a cycloalkenyl ring optionally substituted. R9 is hydrogen, optionally substituted alkyl, C (0) R18, -C (0) 0R20 or -S (0) 2R23; R10, R11, R12, R13 and R19 are selected as in (a) or (b) as follows: (a) R10, R11, R12, R13 and R19 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R11 and R12 or R12 and R19, together with the atoms to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and the others of R10, R11, R12, R13 and R19 are selected as in (a), above; R14, R1 ?, Rld, R17 and R18 are selected as in (a) or (b) as follows: (a) R14, R15, Rld, R17 and R18 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R15 and Rld, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R14, R15, Rld, R17 and R18 are selected as in (a) above; R20, R21, R22 and R24 are selected as in (a) or (b) as follows: (a) R20, R21, R22 and R24 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl optionally substituted, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R21 and R22, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or an optionally substituted heteroaryl ring, and the others of R20, R21, R22 and R24 are selected as (a) above; R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; each of Rx-R24 and R30-R3d, when substituted, are substituted with one or more substituents, each independently selected from Q1; each Q1 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing from 1 to 2 double bonds, alkynyl containing from 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, -OR70, -SR70, -Rd0-, C (J) R71, -Rd0 -N (R70) C (J) R71, -OC (0) R71, -R60 ~ N (R75) (R7d), -N + (R77) 3, -P (R78) 2, - P (0) (R78) ) 2, -OP (O) (R78) 2, -N (R70) S (O) 2R71, -S (0) 2R71, -S (0) R82, -OS (0) R83, -OS (0) 2R83 or -Si (R83) 3; two groups Q1, which replace atoms in a 1,2 or 1,3 configuration, together with the carbon atoms to which they are attached form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; or each Q1 is independently substituted or unsubstituted with one or more substituents each independently selected from Q2; each Q2 is independently selected from halo, pseudohalo, oxo, thioxo, cyano, thiocyano, isocyano, nitro, azido, alkyl, haloalkyl, alkenyl containing from 1 to 2 double bonds, alkynyl containing from 1 to 2 triple bonds, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, alkylidene, arylalkylidene, aryloxyarylcarbonylamino, hydroxycarbonylalkylthio, halosulfonyl, -OR70, -SR70, -Rd0-C (J) R71, -R60- N (R70) C (J) R71, - 0C (0) R71, -R60-N (R7S) (R7d), -N + (R77) 3, -P (R78) 2, - P (0) (R78) 2, - OP (0) (R78) 2, -N (R70) S (0) 2R71, -S (0) 2R7x, -S (0) R82, -OS (0) R83, -OS (0) 2R83 or -Si (R83) 3; two Q2 groups, which replace atoms in a 1,2 or 1,3 configuration, together with the carbon atoms to which they are attached form a cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring or heterocyclyl ring; each J is independently O, S or -NR70; each Rd0 is independently a direct bond or alkylene; each R70 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl or heteroaralkyl; each R71 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, haloalkyl, heterocyclylalkyl, heteroalkyl, -OR72, or -N (R73) R74; R72, R73 and R74 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R73 and R74, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; R75 and R76 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or R75 and R7S, together with the nitrogen atom to which they are attached, form a heterocyclyl ring or heteroaryl ring; each R77 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R78 is alkyl, heteroaryl, heterocyclyl, aryl, -OR79 or -N (R80) R81; R79 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R80 and R81 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R80 and R81, together with the nitrogen atom to which they are attached, form a heterocyclyl or ring. heteroaryl ring; R82 is alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl or -OR83; and each R83 is independently alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; as a simple isomer, a mixture of isomers, or as a racemic mixture of isomers; or as a solvate or polymorph; or as a prodrug; or as a pharmaceutically acceptable salt thereof.

47. A method for treating, preventing, or improving one or more symptoms of a disease or disorder in which fernesoid receptor X activity is involved, characterized in that it comprises administering to a subject in need thereof an effective amount of a compound in accordance with as in claims 1-46.

48. The method according to claim 47, characterized in that the disease or disorder is selected from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, atherosclerotic disease events, atherosclerotic cardiovascular disease, syndrome X, diabetes mellitus, type II diabetes, insulin insensitive diabetes, hyperglycemia, cholestasis and obesity.